2. Gene candidates without plausible pathway in relation to ADHD.

hIn this article, we collect genes with mechanisms whose pathway of action in relation to ADHD is not comprehensible to us.
This article is currently under review. Genes with a 1. as leading digit have not yet been screened for mechanisms of action in relation to ADHD.

Genes with mechanisms whose mode of action in relation to ADHD is not comprehensible to us
Genes whose pathway of action in relation to ADHD we have not yet reviewed
Non-protein coding genes: RNA genes

Genes with mechanisms whose mode of action in relation to ADHD is not comprehensible to us

2.24. CFTR, ciliary neurotrophic factor receptor gene, CNFTR (chromosome 9p13.3)

Other names: CF Transmembrane Conductance Regulator; DJ760C5.1; TNR-CFTR; CFTR/MRP; ABC35; ABCC7; MRP7; Cystic Fibrosis Transmembrane Conductance Regulator; Channel Conductance-Controlling ATPase; CAMP-Dependent Chloride Channel; CF; Cystic Fibrosis Transmembrane Conductance Regulator, ATP-Binding Cassette (Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulator (ATP-Binding Cassette Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulating; ATP-Binding Cassette Sub-Family C, Member 7; ATP-Binding Cassette Sub-Family C Member 7; EC 3.6.3.49; EC 5.6.1.6; EC 3.6.3

The protein CFTR encodes a member of the ATP-binding cassette transporter (ABC) superfamily. CFTR functions as a chloride channel, making it unique among members of this protein family, and controls the secretion and absorption of ions and water in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP binding by the nucleotide-binding domains, and ATP hydrolysis. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a protein sessile on the surface of cells called a chloride channel. Mutations in the CFTR gene in humans result in the absence or impaired function of the channel, among others, which can cause cystic fibrosis (cystic fibrosis) and congenital aplasia of the vas deferens (CAVD).Thus, CFTR is an epithelial ion channel that plays an important role in regulating epithelial ion and water transport, fluid homeostasis (including airway). CFTR mediates the transport of chloride ions across the cell membrane. Chloride channels are a family of anion-selective channels involved in a variety of biological processes, including regulation of neuronal, skeletal, cardiac, and smooth muscle excitability, cell volume regulation, transepithelial salt transport, and acidification of intracellular and extracellular compartments. CFTR channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3)(-); selectivity depends on extracellular chloride concentration. CFTR also exerts its function by modulating the activity of other ion channels and transporters. CFTR contributes to the regulation of pH and ion content of the surface fluid layer of the respiratory tract and thus plays an important role in the defense against pathogens. CFTR modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating cell surface expression of the ENaC complex. CFTR inhibits the activity of the ENaC channel containing SCNN1A, SCNN1B, and SCNN1G subunits, as well as the activity of the ENaC channel containing SCNN1D, SCNN1B, and SCNN1G subunits, but not the ENaC channel containing SCNN1A, SCNN1B, and SCNN1G subunits. CFTR can regulate bicarbonate secretion and recovery in epithelial cells by regulating the transporter SLC4A7. CFTR can inhibit the chloride channel activity of ANO1. CFTR plays a role in chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation.¹
CFTR is associated with

Cystic fibrosis
- Cystic fibrosis correlates with increased L-dopa levels in blood and urine.² This is an indication of a link between cystic fibrosis and dopamine balance. However, cystic fibrosis can have various genetic (co-)causes, so that a conclusion to CFTR is not necessarily given.
Congenital bilateral aplasia of the vas deferens
Cystic Fibrosis
- Cystic fibrosis is the most common fatal genetic disorder in populations of Northern European descent.
- The most common mutation in cystic fibrosis, DeltaF508, results in impaired folding and transport of the encoded protein. Several pseudogenes have been identified in the human genome.

Related Signal Paths:

wtCFTR
delta508-CFTR traffic / generic scheme (standard and CF)
IL-1 Family Signaling Pathways
Enzyme binding
PDZ domain binding

Paralog: ABCC4

OMIM: Ciliary neurotrophic factor receptor gene CNFTR

CFTR (CNFTR) is a candidate gene for ADHD.³
CFTR correlates with cystic fibrosis, which is associated with increased ADHD symptoms.⁴⁵

2.48. FADS2, FATTY ACID DESATURASE 2 (chromosome 11q12.2)

Other names: D6D; SLL0262; FADSD6; TU13; DES6; acyl-CoA 6-desaturase; delta-6-desaturase; LLCDL2; linoleoyl-CoA desaturase (delta-6-desaturase)-like 2; delta(6) fatty acid desaturase; delta-6 fatty acid desaturase; delta(6) desaturase; delta-6 desaturase; EC 1.14.19.3; EC 1.14.19

The enzyme FADS2 removes two hydrogen atoms from a fatty acid, forming a carbon-carbon double bond.
FADS2 belongs to the family of fatty acid desaturase (FADS) genes. Desaturase enzymes regulate the unsaturation of fatty acids by introducing double bonds between specific carbons of the fatty acyl chain. FADS family members are considered fusion products consisting of an N-terminal cytochrome b5-like domain and a C-terminal membrane-spanning desaturase portion, both characterized by conserved histidine motifs. This gene is clustered with family members on 11q12-q13.1; based on the similar exon/intron organization, this cluster is thought to have arisen evolutionarily by gene duplication. FADS2 is involved in the biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3), acting as a fatty acid acyl coenzyme A (CoA) desaturase that introduces a cis-double bond at carbon 6 of the fatty acyl chain. FADS2 catalyzes the first and rate-limiting step in this metabolic pathway, namely the desaturation of LA (18:2n-6) and ALA (18:3n-3) to gamma-linolate (GLA) (18:3n-6) and stearidonate (18:4n-3), respectively (PubMed:12713571). Subsequently, in the n-3 HUFA series biosynthetic pathway, FADS2 desaturates tetracosapentaenoate (24:5n-3) to tetracosahexaenoate (24:6n-3), which is then converted to docosahexaenoate (DHA) (22:6n-3), an important lipid for nervous system function. FADS2 desaturates hexadecanate (palmitate) to generate 6Z-hexadecenoate (sapienate), a fatty acid unique to humans and a major component of human sebum. It is associated with the development of acne and may have potent antibacterial activity. FADS2 can desaturate (11E)-octadecenoate (trans-vaccenoate, the predominant trans-fatty acid in human milk) at carbon 6, resulting in (6Z,11E)-octadecadienoate. In addition to delta-6 activity, FADS2 exhibits delta-8 activity with a slight propensity toward n-3 fatty acyl-CoA substrates.⁶
FADS2 is associated with:

Fetal Akinesia Deformation Sequence 4
Hyperlipoproteinemia, type V

Related metabolic and signaling pathways:

Alpha-linolenic acid (ALA)
Arachidonate biosynthesis III (6-desaturase, mammals)
Iron ion binding
Oxidoreductase activity acting on paired donors, where oxidation of one donor pair leads to the reduction of molecular oxygen to two water molecules

Paralog: FADS3

OMIM: FATTY ACID DESATURASE 2; FADS2

The FADS2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.039.⁷

2.52. MTA3, METASTASIS-ASSOCIATED GENE 3 (chromosome 2)

Additional names: Metastasis Associated 1 Family Member 3; KIAA1266; Metastasis Associated Gene Family, Member 3; Metastasis-Associated Protein MTA3

The protein MTA3 appears to be associated with cellular circulation.
MTA3 is thought to activate histone deacetylase binding activity, transcriptional coactivator activity, and transcriptional corepressor activity. MTA3 is involved in the negative regulation of transcription, DNA-templated. MTA3 is found in the nucleoplasm and is part of the NuRD complex. MTA3 plays a role in maintaining normal epithelial architecture by repressing SNAI1 transcription in a histone deacetylase-dependent manner, thereby regulating E-cadherin levels. MTA3 contributes to transcriptional repression by BCL6.⁸
MTA3 is associated with

Pyloric stenosis
- Narrowing of the stomach outlet
Hutchinson-Gilford progeria syndrome
- massive aging process (progeria) of skin, skeleton and blood vessels, which starts in early childhood

Related metabolic pathways:

Signal transduction
DNA-binding transcription factor activity
Chromatin binding

Paralog: MTA1

OMIM: METASTASIS-ASSOCIATED GENE 3; MTA3

SNP: rs930421 position: 42834743; exon of MTA3 ⁹
p: 5.64E-06
Associated with all ADHD symptoms
SNP: rs6719977 Position: 42839307; Within 2 kb downstream of MTA3 ⁹
p: 1.67E-06
Associated with hyperactivity and impulsivity

2.68. FHIT, FRAGILE HISTIDINE TRIAD GENE (chromosome 3p14.2)

Other names: Fragile Histidine Triad Diadenosine Triphosphatase; AP3Aase; Bis(5’-adenosyl) triphosphatase; FRA3B; Diadenosine 5’,5’’’-P1,P3-triphosphate hydrolase; Adenylylsulfate ammonia adenylyltransferase; Adenosine 5’-monophosphoramidase FHIT; Dinucleoside triphosphatase; Adenylyl sulfatase; AP3A hydrolase; Fragile histidine triad protein; Fragile histidine triad genes; Fragile histidine triad; EC 3.6.1.29; EC 2.7.7.51; EC 3.9.1.-; EC 3.6.2.1

The protein FHIT is a P1-P3-bis(5’-adenosyl) triphosphate hydrolase involved in purine metabolism.
Aberrant transcripts of this gene were found in about half of all esophageal, gastric and colon cancers. FHIT acts as a tumor suppressor, including synergistically with the tumor suppressor VHL, and protects against chemically induced lung cancer and in HER2/neu-induced breast cancer. This gene encompasses the FRA3B common fragile site on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts. In fact, aberrant transcripts of this gene have been found in approximately half of all esophageal, gastric, and colon cancers. FHIT possesses dinucleoside triphosphate hydrolase activity. FHIT cleaves P(1)-P(3)-bis(5’-adenosyl) triphosphate (Ap3A) to AMP and ADP. FHIT can hydrolyze P(1)-P(4)-bis(5’-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. FHIT shows adenylyl sulfatase activity and hydrolyzes adenosine 5’-phosphosulfate to yield AMP and sulfate. FHIT shows adenosine 5’-monophosphoramidase activity, hydrolyzes purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5’-monophosphoramidate (AMP-NH2) to give AMP and NH2. FHIT displays adenylyl sulfate ammonia adenylyltransferase, which catalyzes the ammonolysis of adenosine 5’-phosphosulfate, resulting in the formation of adenosine 5’-phosphoramidate. FHIT catalyzes the ammonolysis of adenosine 5’-phosphorus fluoridate and diadenosine triphosphate. FHIT modulates transcriptional activation by CTNNB1, thereby contributing to the regulation of expression of genes important for cell proliferation and survival, such as CCND1 and BIRC5. FHIT plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. FHIT inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. The induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5’-adenosyl) triphosphate or related compounds, but does not require its catalytic activity. It may derive in part from the mitochondrial form, which sensitizes low-affinity Ca(2+) transporters and promotes mitochondrial calcium uptake. FHIT acts as a tumor suppressor.¹⁰
FHIT is associated with

Renal cell carcinoma, non papillary
sporadic breast cancer

Related Signal Paths:

Endometrial cancer
small cell lung cancer
identical protein binding hydrolase activity

Paralog: HINT1

OMIM: FRAGILE HISTIDINE TRIAD GENE; FHIT

ADHD correlates with SNP rs6791644 60746148, intron of FHIT⁹ as well as rs3772475¹¹.

2.80. TMEM161B; TRANSMEMBRANE PROTEIN 161B

Other names: MGC33214; FLB3342; PRO1313

The protein TMEM161B appears to

Enable nucleic acid binding activity
to be involved in DNA integration
to be an integral part of the cell membrane

TMEM161B protein is essential for the maintenance of normal cardiac rhythm in the developing heart and for neonatal survival. Inhibits potassium and calcium currents in cardiomyocytes, contributing to timely repolarization of the action potential, thereby maintaining a normal heart rhythm.¹²

TMEM161B is associated with:

Brachial plexus neuritis
Bruxism
Related metabolic pathways: Nucleic acid binding.

Paralog: TMEM161A

TMEM161B is considered a candidate gene for depression and for personality traits.¹³
TMEM161B is a candidate gene for ADHD.¹⁴

2.83. SNORC, Secondary Ossification Center Associated Regulator Of Chondrocyte Maturation

Other names: ASCL830; C2orf82; UNQ830; Secondary Ossification Center-Associated Regulator Of Chondrocyte Maturation Protein; Small Novel Rich In Cartilage; Protein SNORC; Chromosome 2 Open Reading Frame 82; Uncharacterized Protein C2orf82

Snorc is a small cartilage-specific transmembrane chondroitin sulfate proteoglycan.
Snorc is ¹⁵

involved in cartilage development
found in the extracellular area
integral part of the membrane
active in the cell periphery.
highly conserved in mammals
has orthologs in all vertebrate subgroups.

During development, expression is highest in the proliferating and prehypertrophic zones. In adult articular cartilage, expression was restricted to the non-calcified zone. Snorc is coexpressed with Sox9, Acan, and Col2a1 and upregulated by BMP-2.¹⁶

Snorc finds itself

in the collagen-containing extracellular matrix
in the cytoplasm

In ADHD, SNORC expression appears to be decreased and methylation increased.¹⁷

2.88. B4GALT2, UDP-GAL:BETA-GlcNAc BETA-1,4-GALACTOSYLTRANSFERASE, POLYPEPTIDE 2

The B4GALT2 protein is one of seven beta-1,4-galactosyltransferases (beta4GalT). These are membrane-bound type II glycoproteins that appear to be specific exclusively for the donor substrate UDP-galactose. All transfer galactose in a beta1,4 bond to similar acceptor sugars: GlcNAc, Glc, and Xyl.
B4GalT2 serves

Metabolism and Transport to the Golgi and Subsequent Modification.
Galactosyltransferase activity
Synthesis of complex N-linked oligosaccharides in many glycoproteins as well as the carbohydrate components of glycolipids
N-acetyllactosamine synthase activity
Its substrate specificity is affected by alpha-lactalbumin, but it is not expressed in lactating breast tissue.

Three transcript variants encoding two different isoforms have been found for this gene.
B4GALT2 is associated with

Ehlers-Danlos syndrome
- Ehlers-Danlos syndrome was observed by us in ADHD more often than average

OMIM: B4GALT2, UDP-GAL:BETA-GlcNAc BETA-1,4-GALACTOSYLTRANSFERASE, POLYPEPTIDE 2

For B4GALT2, one study found an alteration in expression in ADHD.¹⁸
This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

2.92. TRIO, Trio Rho Guanine Nucleotide Exchange Factor

Additional names: ARHGEF23; Triple Functional Domain (PTPRF Interacting); Triple Functional Domain Protein; PTPRF-Interacting Protein; EC 2.7.11.1; MEBAS; RD44; MRD63; Tgat; TRIPLE FUNCTIONAL DOMAIN

Some isoforms of calirin and trio colocalized with immature secretory granules in mouse and rat neuroendocrine cells and modulated their cargo secretion.
Overexpression of their N-terminal GEF domains enhanced secretion from immature granules such that the cells lost their secretory cargo in the absence of secretory tagogum (the agent that caused their secretion). This response required GEF activity and was mimicked by the calirin/Trio substrates Rac1 and RhoG. Selective pharmacological inhibition of endogenous GEF activity reduced secretagogue-independent release of hormone precursors and resulted in accumulation of the product peptide in mature secretory granules. Modulation of cargo secretion from immature granules by calirin/TRIO provides secretory cells with additional control over the amounts of peptide released and expands the range of physiological responses that can be triggered. .
TRIO (amino acids 1227-1407) catalyzes the nucleotide exchange for Rac1. The all-alpha-helical protein has a structure very different from other exchange factors. Based on site-directed mutagenesis, the authors identified functionally important residues of the DH domain. They are all highly conserved and located in close proximity on 2 alpha helices. In addition, Liu et al. (1998) discovered a unique ability of the pleckstrin homology (PH) domain to enhance nucleotide exchange in DH domain-containing proteins.²⁰
TRIO is associated with

mental disability
- TRIO-associated intellectual disability is characterized by:²¹
  - delayed acquisition of motor and language skills
  - mild to borderline mental retardation
  - neurobehavioral problems, including:
    - autistic traits or autism spectrum disorder
      - ADHD
    - Aggression)
- often continue to occur:
  - Neonatal or infant feeding difficulties
    - e.g., poor sucking, impaired bottle feeding, and failure to thrive
  - Microcephaly
  - Hand and tooth anomalies
  - be striking facial features

OMIM: TRIO, TRIPLE FUNCTIONAL DOMAIN

In TRIO, one study found a change in expression in ADHD.¹⁸

2.94. SYNE1, SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1

Other names: Nesprin-1; Enaptin; MYNE1; Myocyte Nuclear Envelope Protein 1; KIAA0796; DJ45H2; C6orf98; SCAR8; ARCA1; Nesp1; CPG2; 8B; Spectrin Repeat Containing, Nuclear Envelope 1; Synaptic Nuclear Envelope Protein 1; KASH Domain-Containing Protein 1; SYNE-1B; KASH1; Nuclear Envelope Spectrin Repeat Protein 1; Nuclear Envelope Spectrin Repeat-1; Chromosome 6 Open Reading Frame 98; Synaptic Nuclei Expressed Gene 1; CPG2 Full Length; EC 4.2.1.49; EC 4.3.1.3; Nesprin 1; KIAA1262; KIAA1756; Myne-1; Syne-1; EDMD4; AMC3; AMCM

SYNE1 is one of the largest genes in the human genome and therefore particularly susceptible to mutations or gene defects. Its longest isoform comprises 146 exons, which code for the synaptic nuclear envelope protein 1 with 8797 amino acids. Synaptic nuclear envelope protein 1 (Nesprin 1, nuclear envelope spectrin 1) belongs to the spectrin family of structural proteins whose common function is to connect the plasma membrane to the actin cytoskeleton. SYNE1 encodes a protein that is important for maintaining the cerebellum - the part of the brain that coordinates complex body movements. Truncated recessive mutations in SYNE1 result in a slowly progressive, relatively pure cerebellar ataxia with few extracerebellar symptoms (spinocerebellar ataxia, autosomal recessive 8; SCAR8/autosomal recessive cerebellar ataxia type 1, ARCA1)²²

SYNE1 is a Spectrin repeat-containing protein expressed in skeletal and smooth muscle and peripheral blood lymphocytes and localized to the nuclear membrane. SYNE1 forms a connecting network between organelles and the actin cytoskeleton to maintain subcellular spatial organization. As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, SYNE1 is involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces to the nuclear envelope and in the movement and positioning of the nucleus. SYNE1 may be involved in nuclear centrosome attachment and nuclear migration in neural progenitors, implying an association of the LINC complex with SUN1/2 and probably an association with cytoplasmic dynein-dynactin motor complexes. SYNE1 and SYNE2 may act redundantly. SYNE1 is required for centrosome migration to the apical cell surface during early cilia genesis. SYNE1 may be involved in nuclear remodeling during sperm head formation in spermatogenesis.²³
SYNE1 is associated with

Spinocerebellar ataxia, autosomal recessive 8
- also called autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce
Arthrogryposis Multiplex Congenita 3, Myogenic Type

Symptome of SYNE1 ataxia:

Gait and limb ataxia
cerebellar dysarthria
Changes in the antisaccade paradigm
- these could be related to working memory problems²⁴

Related Signal Paths:

Cell cycle
Mitosis
Meiosis
RNA binding
Nucleotide binding

Paralog: DMD

OMIM: SYNE1, SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1

In SYNE1, one study found a change in expression in ADHD.¹⁸ One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

2.96. BMPR1B; Bone morphogenetic protein receptor type-1B

Other names: CDw293; ALK6; Bone Morphogenetic Protein Receptor, Type IB; Bone Morphogenetic Protein Receptor Type-1B; BMP Type-1B Receptor; EC 2.7.11.30; BMPR-1B; Serine/Threonine Receptor Kinase; Activin Receptor-Like Kinase 6; CDw293 Antigen; EC 2.7.11; ALK-6; BDA1D; AMD3; AMDD; BDA2; CDw293, Cluster of differentiation w293

BMPR1B is a member of the transmembrane serine/threonine kinase family of bone morphogenetic protein (BMP) receptors. The ligands of this receptor are BMPs of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins relay their signals by forming heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors but require their respective type I receptors for signal transduction, whereas type I receptors require their respective type II receptors for ligand binding,.
The BMPR1B receptor plays a role in the formation of the middle and proximal phalanges.²⁶
BMPR1B is found in prepartilaginous condensations (in the chick embryo). BMPR1B is the major signal transducer in these condensations. BMPR1B transmits GDF5 more effectively than BMPR1A. While BMPR1A-KO mice die at an early embryonic stage, BMPR1B-KO mice are viable.²⁷
BMP signaling is involved in the formation of the pre-ebellar mossy fiber nuclei that give rise to the cerebellar mossy fibers.²⁸
BMPR1B is associated with

primary pulmonary hypertension
Brachydactyly²⁹³⁰³¹
Breast Cancer³²
du Pan-acromesomelic dysplasia and Grebe dysplasia³³³⁴

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

2.285. HAS3, Hyaluronan Synthase 3

Other names: Hyaluronic Acid Synthase 3; Hyaluronate Synthase 3; HA Synthase 3; EC 2.4.1.212

The enzyme HAS3 is involved in the synthesis of the unbranched glycosaminoglycan hyaluronan or hyaluronic acid, which is a major component of the extracellular matrix. HAS3 is one of three isoenzymes responsible for cellular hyaluronan synthesis. HAS3 catalyzes the attachment of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer. Hyaluronan is a major component of most extracellular matrices, plays a structural role in tissue structure, and regulates cell adhesion, migration, and differentiation.³⁵
Related Signal Paths:

Glycosaminoglycan metabolism
Glycosaminoglycan metabolism
Hyaluronan synthase activity

Paralog: HAS2

Hyaluronan, like dopamine and serotonin, is increased in blood in neonatal hyperoxia, and dopamine is also increased in urine. Hyperoxia increased mRNA expression in the dorsal brainstem of HAS3 serotonin 1A receptor, dopamine D1 receptor, and dopsmin D2 receptor.³⁶³⁷
Extracellular hyaluronate pressure, shaped by cellular connective members, drives tissue morphogenesis.³⁸
Extracellular and intracellular hyaluronan binds to hyaluronan-binding proteins such as CD44, RHAMM, CDC37, and USP17, thus influencing cell behavior. Intracellular hyaluronan appears to have important regulatory functions during the cell cycle, cell motility, RNA translation and splicing, and autophagy.³⁹
Oxidative stress triggered by tobacco smoke leads to inflammation and depolymerization of hyaluronan.⁴⁰

One study found HAS3 to be one of the 51 most likely gene candidates for ADHD.²⁵

2.103. ITIH3, Inter-Alpha-Trypsin Inhibitor Heavy Chain 3

Other names: Inter-Alpha-Trypsin Inhibitor Heavy Chain H3, H3P, Inter-Alpha (Globulin) Inhibitor, H3 Polypeptide, Pre-Alpha (Globulin) Inhibitor, H3 Polypeptide

The protein ITIH3 is a subunit of the heavy chain of the pre-alpha-trypsin inhibitor complex. By binding hyaluronic acid, this complex can stabilize the extracellular matrix. It appears to form response to increased platelet cytosolic Ca2+ and cell adhesion_cell-matrix glycoconjugates. It is associated with serine-type endopeptidase inhibitor activity and endopeptidase inhibitor activity.⁴¹

ITIH3 is associated with

Schizophrenia
- rs2535629 showed a better response to clozapine⁴²
Depression
- ITIH3 rs2535629 significantly affects the expression of ITIH4 and GLT8D1. The expression of GLT8D1 was significantly increased in depression.⁴³
Autism Spectrum Disorder⁴⁴
Cancer⁴⁰
Myocardial Infarction⁴⁵

Related Signal Paths:

oxidative stress⁴⁰

Decreased ITIH3 protein levels were found in the plasma of cigarette smokers⁴⁰

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵ Another study found no evidence of association with ADHD for the ITIH3 polymorphism rs52535629⁴⁶

2.113. ATP2C2, ATPase Secretory Pathway Ca2+ Transporting 2

Other names: SPCA2, KIAA0703, Secretory Pathway Ca(2+)-Transporting ATPase Type 2, ATPase, Ca++ Transporting, Type 2C, Member 2, Calcium-Transporting ATPase Type 2C Member 2

The protein ATP2C2 facilitates the activity of the P-type calcium transporter and the P-type manganese transporter and is thereby involved in transmembrane transport of calcium ions, cellular calcium ion homeostasis, and manganese ion transport. ATP2C2 is an ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both of which are essential cofactors for the processing and transport of newly synthesized proteins in the secretory pathway. Within a catalytic cycle, ATP2C2 takes up Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and releases them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is accompanied by transient phosphorylation that shifts the conformation of the pump from an inward to an outward state ATP2C2 induces Ca(2+) influx independently of its ATP-driven pump function. ATP2C2 interacts with the Ca(2+) channel ORAI1 at the basolateral membrane of mammary epithelial cells and mediates Ca(2+) influx independently of the Ca(2+) content of the endoplasmic reticulum or Golgi stores. ATP2C2 may facilitate transepithelial transport of large amounts of Ca(2+) for milk secretion by activating Ca(2+) influx channels at the plasma membrane and active Ca(2+) transport at the Golgi apparatus.⁴⁷

ATP2C2 is associated with

specific language disorders
- A rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene is elevated in speech disorders. This rare variant appears to affect the ATPase activity of SPCA2.⁴⁸ Another study identifies c.2465C>T for this purpose⁴⁹
Dyslexia⁵⁰
- ATP2C2 rs11860694 modulates phonological short-term memory in language disorders⁵¹

One study found ATP2C2 as one of the 51 most likely gene candidates for ADHD.²⁵ Another study found it among 96 candidate genes.⁵² One review considers ATP2C2 to be part of a neurological network involved in the directional growth of neurites, which appears to have a strong involvement in ADHD.⁵³

2.118. MPP6, MAGUK p55 subfamily member 6

Other names: VAM-1; P55T; MPP6; Membrane Protein, Palmitoylated 6 (MAGUK P55 Subfamily Member 6); Protein Associated With LIN7 2, MAGUK Family Member; Membrane Palmitoylated Protein 6; MAGUK P55 Subfamily Member 6; Protein PALS2; VAM1; Membrane Protein, Palmitoylated 6; Protein Associated With Lin7; VELI-Associated MAGUK 1; Veli-Associated MAGUK 1; MAGUK Protein P55T

The protein MPP6 is a member of the family of peripheral membrane-associated guanylate kinases (MAGUK, membrane-associated guanylate kinase homologues). These are involved in tumor suppression and receptor clustering by forming multiprotein complexes containing various groups of transmembrane, cytoskeletal, and cytoplasmic signaling proteins⁵⁴
MPP6 appears to be involved in myelination.⁵⁵
A GWAS identified involvement of MPP6 in sleep disorders⁵⁶

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

2.123. PALB2, Partner and localizer of BRCA2

Other names: PALB2, FANCN

The protein PALB2 gene is responsible for genome maintenance (repair of double-strand breaks). PALB2 binds and colocalizes with Breast Cancer 2 Early Onset Protein (BRCA2) in nuclear foci and likely enables stable intranuclear localization and accumulation of BRCA2.⁵⁷

PALB2 gene is associated with

increased risk of breast cancer
familial pancreatic cancer
Ovarian Cancer
Fanconi anemia
reduced fertility (proven in mice)

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

2.124. ZNF385D, Zinc Finger Protein 385D

Other names: Zinc Finger Protein 659, ZNF659, FLJ22419

The protein ZNF385D enables sequence-specific double-stranded DNA binding activity. ZNF385D is thought to be active in the nucleus⁵⁸ and is found primarily in the cerebellum and retina.
ZNF385D is associated with

Reading disability⁵⁹
- ZNF385D was found to be a predictor of total fiber tract volume in both hemispheres as well as global brain volume
Dyscalculia
ADHD
Schizophrenia; negative symptoms⁶⁰
- rs2060531
- rs9869330

One study found ZNF385D to be one of the 51 most likely candidate genes for ADHD.²⁵ ZNF385D rs11719664 was identified as a candidate gene for ADHD in another 2008 study. .⁶¹

2.126. CHMP7, Charged Multivesicular Body Protein 7

Other names: Chromatin-Modifying Protein 7, CHMP Family, Member 7, MGC29816

The protein CHMP7 is involved in the late transport of endosomes to vacuoles, in the abscission of the midbody, and in mitotic nuclear division. CHMP7 is found in the cytosol, nuclear envelope, and nucleoplasm. CHMP7 is part of the ESCRT III complex. CHMP7 colocalizes with chromatin. CHMP7 is required for recruitment of the ESCRT III complex to the nuclear envelope during late anaphase. Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle degradation during late anaphase. CHMP7 is recruited to the newly forming nuclear envelope during anaphase by LEMD2. CHMP7 plays a role in the endosomal sorting pathway.⁶²
CHMP7 is associated with

cerebellar ataxia type 48
ADHD
spinal and bulbar muscular atrophy⁶³

One study found CHMP7 as one of the 51 most likely candidate genes for ADHD.²⁵ Another study found CHMP7 rs2294123, G→T as one of 65 ADHD candidate gene variants.⁶⁴
CHMP7-KO zebrafish showed significant hyperactivity over a 24-hour period 6 days after fertilization compared with chmp7+/+, although this effect did not persist into adolescence and adulthood and was significantly reduced by methylphenidate. CHMP7+/- fish showed significantly reduced total brain volume.⁶⁵

2.128. MUCL3, DPCR1, Human diffuse panbronchiolitis critical region 1, Real Time PCR Primer Set

Other names: Mucin Like 3, C6orf37, PBLT, DPCR1, Diffuse Panbronchiolitis Critical Region Protein 1, Diffuse Panbronchiolitis Critical Region 1, Mucin-Like Protein 3, BCX105N19.6

The protein MUCL3 is thought to be localized in the cytoplasm and plasma membrane. It appears to be an integral component of the membrane. MUCL3 possibly modulates NF-kappaB signaling and plays a role in cell growth.⁶⁶
MUCL3 is associated with

Panbronchiolitis, diffuse
spinocerebellar ataxia, autosomal recessive 8

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

2.129. PIWIL4, Piwi Like RNA-Mediated Gene Silencing 4

Other names: HIWI2, Piwi-Like Protein 4, FLJ36156, Miwi2

The protein PIWIL4 belongs to the Argonaute family of proteins that play a role in the development and maintenance of germline stem cells. PIWIL4 plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for germline integrity. PIWIL4 acts through the piRNA metabolic process, which mediates the repression of transposable elements during meiosis through the formation of complexes of piRNAs and Piwi proteins, and controls the methylation and subsequent repression of transposons. PIWIL4 directly binds piRNAs, a class of RNAs with 24 to 30 nucleotides generated by a Dicer-independent mechanism and derived primarily from transposons and other sequence repeat elements. PIWIL4 is associated with secondary piRNAs antisense. PIWIL2/MILI is required for this association. The piRNA process acts upstream of known mediators of DNA methylation. PIWIL4 plays a key role in the piRNA amplification loop, also called the ping-pong amplification cycle, by acting as a “slicer-incompetent” component that loads cleaved piRNAs from the “slicer-competent” component PIWIL2 and directs them to genomic transposon loci in the nucleus. PIWIL4 may be involved in the chromatin-modifying pathway by inducing ‘Lys-9’ methylation of histone H3 at some loci. PIWIL4 further plays a role in regulating somatic cell activities and pancreatic beta cell function and insulin secretion. PIWIL4 is involved in the maintenance of cell morphology and functional integrity of the retinal epithelium through the Akt/GSK3alpha/beta signaling pathway. PIWIL4, when overexpressed, acts as an oncogene by inhibiting apoptosis and promoting cell proliferation in tumors.⁶⁷
PIWIL4 is associated with

Spermatogenic Failure (male infertility)
Cervical cancer.

One study found PIWIL4 to be one of the 51 most likely gene candidates for ADHD.²⁵

2.130. AK8, adenylate kinase 8

Other names: C9orf98, ATP-AMP transphosphorylase 8, FLJ32704, AK 8

The protein AK8 enables AMP binding activity and kinase activity for nucleobase-containing compounds. AK8 is involved in nucleoside diphosphate phosphorylation and nucleoside triphosphate biosynthesis process.
AK8 is found in the 9+2 motile cilium. AK8 is a nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. AK8 has the highest activity toward AMP and weaker activity toward dAMP, CMP, and dCMP. AK8 further shows broad nucleoside diphosphate kinase activity.⁶⁸

AK8 is associated with reticular dysgenesis.

One study found AK8 to be one of the 51 most likely gene candidates for ADHD.²⁵

2.131. CFAP221, Cilia And Flagella Associated Protein 221

Other names: PCDP1, FAP221, Cilia- And Flagella-Associated Protein 221

The protein CFAP221 probably activates calmodulin-binding activity and appears to be involved in cilia formation. It is probably active upstream of or within CSF circulation, assembly of the motile cilium, and mucociliary clearance.CFAP221 is probably found in the axoneme, extracellular region, and flagella of spermatocytes.⁶⁹ CFAP221 may play an important role in calcium-mediated regulation of dynein activity⁷⁰
CFAP221 is associated with

ciliary dyskinesia
cerebral degeneration

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

Genes whose pathway of action in relation to ADHD we have not yet reviewed

1.132. CEP112, Centrosomal Protein 112

Other names: CCDC46, Coiled-Coil Domain-Containing Protein 46, Centrosomal Protein Of 112 KDa, Centrosomal Protein 112kDa

CEP112 is a coiled-coil domain-containing protein and belongs to the cell division control 42 family of effector proteins. In neurons, it is localized to the cytoplasm of dendrites and is also enriched in the nucleus, where it interacts with the RNA polymerase III transcriptional repressor Maf1 to regulate surface expression of the gamma-aminobutyric acid A receptor. In addition, the protein has been identified as a component of the human centrosome.⁷¹CEP112 is involved in receptor localization to the synapse.((
CEP112 is associated with

Spermatogenic Failure 44 (male infertility)
Spermatogenic Failure 16.(Male Infertility)

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.133. KIF6, Kinesin Family Member 6

Other names: DJ1043E3.1, DJ137F1.4, DJ188D3.1

The protein KIF6 is a member of a family of molecular motors involved in the intracellular transport of protein complexes, membrane organelles, and ribonucleic acid messengers along microtubules. Kinesins function as homodimeric molecules with two N-terminal head domains that move along microtubules and two C-terminal tail domains that interact with the transported cargo either directly or indirectly via adapter molecules. This gene is ubiquitously expressed in coronary arteries and other vascular tissues.
KIF6 is associated with conoran heart disease.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.135. NCKAP5, NCK Associated Protein 5

Other names: NAP5, ERIH1, ERIH2

The protein NCKAP5 is thought to be involved in microtubule bundle formation and microtubule depolymerization, as well as being active at the microtubule plus end.⁷²
NCKAP5 is associated with

ADHD
drug-induced lupus erythematosus

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.136. SPATA33, Spermatogenesis Associated 33

Other names: C16orf55, Spermatogenesis-Associated Protein 33, FLJ31606, Chromosome 16 Open Reading Frame 55

The protein SPATA33 is thought to be active upstream of or within cellular protein localization, fertilization, and flagellar sperm motility. SPATA33 appears to be localized in the sperm mitochondrial envelope and active in the cytoplasm and nucleus.⁷³⁷⁴
SPATA33 is associated with Fanconi anemia, complementation group A.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.137. CDK10, Cyclin Dependent Kinase 10

Other names: PISSLRE, Cyclin-Dependent Kinase (CDC2-Like) 10, Cell Division Protein Kinase 10, Cyclin-Dependent Kinase 10, EC 2.7.11.22

The protein CDK10 belongs to the CDK subfamily of the Ser/Thr protein kinase family. Members of the CDK subfamily are very similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2 and are essential for cell cycle progression. This kinase has been shown to play a role in cell proliferation and its function is restricted to the G2-M phase of the cell cycle. CDK10 is a cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and promotes its proteasomal degradation (in cells). CDK10 is involved in regulating actin cytoskeleton organization by phosphorylating regulators of actin dynamics such as PKN2. CDK10 is a negative regulator of ciliogenesis by phosphorylating PKN2 and promoting RhoA signaling.⁷⁵
CDK10 is associated with

Al-Kaissi Syndrome
Toe syndactyly
Telecanthus
anogenital and renal malformations

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.138. PPP1R11, PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 11

Other names: HCGV, CFAP255, HCG-V, TCTE5, Protein Phosphatase 1 Regulatory Subunit 11, Hemochromatosis Candidate Gene V Protei, E3 Ubiquitin-Protein Ligase PPP1R11, TCTEX5

The protein PPP1R11 is a specific inhibitor of protein phosphatase-1 (PP1) with differential sensitivity to the metal-independent and metal-dependent forms of PP1. PPP1R11 is an atypical E3 ubiquitin-protein ligase that ubiquitinates TLR2 at ‘Lys-754’, leading to its degradation by the proteasome. PPP1R11 plays a role in regulating the release of inflammatory cytokines and the clearance of Gram-positive bacteria, acting in part by ubiquitinating and degrading TLR2.⁷⁶

OMIM: PPP1R11, PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 11

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁵

1.140. NME5, NME/NM23 FAMILY, MEMBER 5

Other names: Nm23-H5, RSPH23, Non-Metastatic Cells 5, Protein Expressed In (Nucleoside-Diphosphate Kinase), Nucleoside Diphosphate Kinase Homolog 5, Inhibitor Of P53-Induced Apoptosis-Beta, Testis-Specific Nm23 Homolog, NDP Kinase Homolog 5, IPIA-Beta, NDK-H 5, Non-Metastatic Cells 5 Protein Expressed In, Radial Spoke 23 Homolog (Chlamydomonas), Radial Spoke 23 Homolog, NM23-H5, NM23H5

The protein NME5 is thought to facilitate nucleoside diphosphate kinase activity. NME5 is thought to be involved in the negative regulation of oxidative stress-induced intrinsic apoptotic signaling and spermatid development. NME5 is thought to be active upstream of or within cilia assembly, epithelial cilia movement involved in extracellular fluid movement, and ventricular system development. NME5 is thought to be found in the cilium. NME5 does not appear to have NDK kinase activity. NME5 protects against cell death by Bax and alters cellular levels of several antioxidant enzymes including Gpx5. NME5 may play a role in spermiogenesis by increasing the ability of late stage spermatids to eliminate reactive oxygen species.⁷⁷
NME5 is associated with

Nemalin myopathy 5
primary ciliary dyskinesia

OMIM: NME5, NME/NM23 FAMILY, MEMBER 5

NME5 is a candidate gene for ADHD.⁷⁸

1.141. ABHD5, ABHYDROLASE DOMAIN-CONTAINING 5

Other names: CGI-58, CGI58, 1-acylglycerol-3-phosphate O-acyltransferase, Lysophosphatidic Acid Acyltransferase, NCIE2, 1-acylglycerol-3-phosphate O-acyltransferase ABHD5, Abhydrolase Domain-Containing Protein 5, Lipid Droplet-Binding Protein CGI-58, EC 2.3.1.51, Truncated Abhydrolase Domain-Containing Protein 5, Abhydrolase Domain Containing 5, IECN2, External Ids for ABHD5 Gene

The ABHD5 protein is defined by, among other things, an alpha/beta hydrolase fold. ABHD5 contains three sequence motifs corresponding to a catalytic triad found in the esterase/lipase/thioesterase subfamily. ABHD5 functions in phosphatidic acid biosynthesis, ABHD5 possibly regulates cellular storage of triacylglycerol by activating the phospholipase PNPLA2 , and is involved in keratinocyte differentiation. ABHD5 regulates lipid droplet fusion.
ABHD5 is a coenzyme A-dependent lysophosphatidic acid acyltransferase that catalyzes the transfer of an acyl group to a lysophosphatidic acid. ABHD5 functions preferentially with⁷⁹

as lipid acceptor
- 1-oleyl-lysophosphatidic acid, followed by
- 1-Palmitoyl lysophosphatidic acid
- 1-Stearoyl lysophosphatidic acid
- 1-Arachidonoyl lysophosphatidic acid
as acyl group donors
- Arachidonoyl-CoA, followed by
- Oleoyl-CoA

The enzyme ABHD5 has a regulatory function in lipid metabolism. Among other things, it stimulates lipolysis.
ABHD5 is expressed in adipose tissue, liver, neurons and epidermis, among others.

In adipose tissue, ABHD5 is bound to perilipin-1. Β-adrenergic stimulation activates protein kinase A, which phosphorylates perilipin-1. This causes dissociation of ABHD5 and perilipin-1, and the unbound ABHD5 then activates adipocyte triglyceride lipase (ATGL). This enzyme catalyzes the first step of lipolysis, the breakdown of triacylglycerol into diacylglycerol. G0S2 acts as an antagonist. Outside adipocytes: ABHD5 interacts with adipophilin (perilipin-2) and perilipin-5, among others. ABHD5 converts lysophosphatidic acid to phosphatidic acid by means of acyl-CoA-dependent lysophosphatidic acid acyltransferase activity (LPAAT).⁸⁰
ABHD5 is associated with Chanarin-Dorfman syndrome, a triglyceride storage disorder with impaired oxidation of long-chain fatty acids, and lipid storage disease.

OMIM: ABHD5, ABHYDROLASE DOMAIN-CONTAINING 5

ABHD5 is a candidate gene for ADHD.⁷⁸

1.142. GMPR2, GUANOSINE MONOPHOSPHATE REDUCTASE 2

Other names: Guanosine 5’-Monophosphate Oxidoreductase 2, GMP Reductase 2, EC 1.7.1.7, GMPR 2, Guanosine Monophosphate Reductase Isolog 3

The enzyme GMPR2 catalyzes the irreversible and NADPH-dependent reductive deamination of guanosine monophosphate (GMP) to inosine monophosphate (IMP). GMPR2 is involved in the recycling of free intracellular bases and purine nucleosides. GMPR2 is involved in the conversion of nucleobase, nucleoside, and nucleotide derivatives of G to A nucleotides and in maintaining the intracellular balance of A and G nucleotides. GMPR2 plays a role in modulating cellular differentiation.⁸¹
GMPR2 is associated with urethra cancer.

OMIM: GMPR2, GUANOSINE MONOPHOSPHATE REDUCTASE 2

GMPR2 is a candidate gene for ADHD.⁷⁸

1.144. BLOC1S2, BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 2

Other names: BLOS2, BLOC-1 Subunit 2, BORCS2, Biogenesis Of Lysosome-Related Organelles Complex 1 Subunit 2, Centrosome Protein Oncogene, MGC10120, FLJ30135, CEAP, Biogenesis Of Lysosome-Related Organelles Complex-1 Subunit 2, 11 KDa Centrosome Associated Protein, Centrosome-Associated Protein, Centrosomal 10 KDa Protein, CEAP11

OMIM: BLOC1S2, BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 2

The BLOC1S2 protein has several functions:⁸²

was found in connection with the centrosome
colocalized with gamma-tubulin
is a protein in the BLOC-1 complex
- plays a role in the formation of lysosomal organelles (e.g. dense granules of platelets and melanosomes)
BLOC-1 complex
- traffics (together with AP-3 complex) membrane protein cargoes into vesicles formed in cell bodies for transport into neurites and nerve terminals.
- is probably also involved (in conjunction with SNARE proteins) in neurite extension
- is part of the BORC complex; possibly relevant in movement and localization of lysosomes at the cell periphery
- may play a role in cell proliferation
BLOC1S2 is associated with
- Hermansky-Pudlak syndrome
- primary autosomal recessive microcephaly (reduced skull size)

Microcephaly is often associated with ADHD.
BLOC1S2 is a candidate gene for ADHD.⁷⁸

1.145. KIAA0319L, KIAA0319-LIKE

Other names: KIAA0319 Like, AAVR, KIAA1837, Dyslexia-Associated Protein KIAA0319-Like Protein, Adeno-Associated Virus Receptor, Polycystic Kidney Disease 1-Related, AAV Receptor Like, KIAA0319-Like, AAV Receptor, AAVRL

OMIM: KIAA0319L, KIAA0319-LIKE

The protein KIAA0319L may be involved in axon guidance through interaction with RTN4R.
KIAA0319L acts as a receptor for adeno-associated viruses and is involved in adeno-associated virus infection through the endocytosis system.⁸³
KIAA0319L is associated with

Dyslexia
limited scleroderma

KIAA0319L is a candidate gene for ADHD.⁷⁸

1.146. FMNL3, Formin Like 3

Other names: WBP3, Formin Homology 2 Domain-Containing Protein 3, Formin-Like Protein 3, DKFZp762B245, MGC45819, FHOD3, WBP-3, FRL2, WW Domain Binding Protein 3, WW Domain-Binding Protein 3, Formin-Like 3, KIAA2014

The protein FMNL3 contains a formin homology 2 domain and shares high sequence identity with the mouse Wbp3 protein. FMNL3 is involved in the regulation of cell morphology and cytoskeletal organization. FMNL3 is required for the control of cell shape and migration as well as developmental angiogenesis. FMNL3 triggers actin cytoskeleton restructuring in quiescent endothelial cells without altering microtubule orientation.⁸⁴
FMNL3 is associated with

malignant breast melanoma
cerebral amyloid angiopathy, Itm2b-related, 2.

FMNL3 is a candidate gene for ADHD.⁷⁸

1.147. CCDC138, Coiled-Coil Domain Containing 138

Other name: FLJ32745

CCDC138 is expressed at low levels in almost all human tissues, including lymphocytes in peripheral blood, fetal thymus, thymus, testis, ovary, feral brain, colon, mammary gland, and bone marrow. Elevated concentrations in some cancer tissues. CCDC138 is a soluble protein that accumulates in the nucleus of a cell. CCDC138 is involved in the initiation of labor in the myometrium.
The protein CCDC138 is associated with⁸⁵

Chromosome 3Q13.31 deletion syndrome
Fundus dystrophy

CCDC138 is a candidate gene for ADHD.⁷⁸

1.148. TMBIM6, Transmembrane BAX Inhibitor Motif Containing 6

Other names: BI-1, BAXI1, TEGT, Transmembrane BAX Inhibitor Motif-Containing Protein 6, Testis-Enhanced Gene Transcript Protein, Testis Enhanced Gene Transcript, Bax Inhibitor 1, BAX Inhibitor 1, BI1

The protein TMBIM6 facilitates endoribonuclease inhibitor activity and ubiquitin-protein ligase binding activity. TMBIM6 is involved in:⁸⁶

inhibits RNA metabolism
inhibits intrinsic apoptotic signaling pathway
inhibits reaction to L-glutamate
modulates the signaling of the unfolded protein response
inhibits autophagy and autophagosome formation, especially in the case of nutrient deficiency
- reduces the survival of cells during starvation
acts upstream of or within the negative regulation of calcium ion transport into the cytosol
Located in the membrane of the endoplasmic reticulum and the mitochondrial membrane
- modulates endoplasmic reticulum calcium homeostasis by acting as a calcium leak channel
Biomarkers for squamous cell carcinoma of the cervix and prostate carcinoma

TMBIM6 is associated with

chronic congestive splenomegaly (an enlargement of the spleen)
Inclusion conjunctivitis (an inflammation of the conjunctiva)

TMBIM6 is a candidate gene for ADHD.⁷⁸

1.149. SV2A, Synaptic Vesicle Glycoprotein 2A

Other names; KIAA0736, SV2

SV2A is one of three related synaptic vesicle proteins. SV2A can interact with synaptotagmin to enhance low-frequency neurotransmission in resting neurons.
SV2A positively regulates vesicle fusion by maintaining the readily releasable pool of secretory vesicles.⁸⁷
SV2A is receptor for

the C.botulinum neurotoxin type A2 (BoNT/A, botA)
the C.botulinum neurotoxin type A1 (probably)

SV2A is associated with:

food-related
Carbamazepine allergy

SV2A is a candidate gene for ADHD.⁷⁸

1.150. TARBP1, TAR (HIV-1) RNA Binding Protein 1

Other names: TRP-185, TRM3, TRMT3, TAR RNA-Binding Protein Of 185 KDa, Probable Methyltransferase TARBP1, TAR RNA-Binding Protein 1, TRP185, TRNA Methyltransferase 3 Homolog (S. Cerevisiae), Tar (HIV-1) RNA Binding Protein 1, TRNA Methyltransferase 3 Homolog 3, TAR (HIV) RNA-Binding Protein 1, TAR RNA Loop Binding Protein, EC 2.1.1.-
External Ids for TARBP1 Gene

TARBP1 is a putative S-adenosyl-L-methionine-dependent methyltransferase that methylates RNA molecules such as tRNAs. In HIV-1 infection, it binds to the loop region of TAR RNA, a region that is also bound by RNA polymerase II. The binding of TARBP1 and RNA polymerase II to HIV-1 TAR RNA is mutually exclusive, suggesting that TARBP1 alone or in combination with HIV-1 Tat can release RNA polymerase II from HIV-1 TAR RNA.⁸⁸
TARBP1 is associated with immunodeficiency diseases.

TARBP1 is a candidate gene for ADHD.⁷⁸

1.151. TATDN3

Other names: TatD DNase Domain Containing 3, Putative Deoxyribonuclease TATDN3, EC 3.1.21.-, EC 3.1.21

The protein TATDN3 probably activates metal ion binding activity and nuclease activity. TATDN3 is thought to be involved in the hydrolysis of nucleic acid phosphodiester bonds and is probably localized in the nucleus.⁸⁹

TATDN3 is a candidate gene for ADHD.⁷⁸

1.152. ALS2CR8, CARF

Other names: Calcium Responsive Transcription Factor, Calcium-Response Factor, NYD-SP24, ALS2CR8, Amyotrophic Lateral Sclerosis 2 Chromosomal Region Candidate Gene 8 Protein, Amyotrophic Lateral Sclerosis 2 (Juvenile) Chromosome Region, Candidate 8, Calcium-Responsive Transcription Factor, Testis Development Protein NYD-SP24, FLJ21579, CaRF

The protein ALS2CR8 is a DNA-binding transcription factor and facilitates DNA-binding activity. ALS2CR8 is involved in the cellular response to potassium ions and in the positive regulation of transcription from the RNA polymerase II promoter in response to calcium ions. ALS2CR8 binds to the consensus calcium response element CaRE1 5’-CTATTTCGAG-3’ sequence. ALS2CR8 is thought to be localized in the granular component and active in the nucleus. CARF is associated with⁹⁰

Amyotrophic lateral sclerosis 2, juvenile
Moyamoya disease 1

ALS2CR8 is a candidate gene for ADHD.⁷⁸ Moyamoya shows ADHD symptoms.

1.153. ST3GAL3

Other names: ST3 beta-galactosides alpha-2,3-sialyltransferase 3; ST3Gal III; SIAT6; CMP-N-acetylneuraminate beta-1,4-galactosides alpha-2,3-sialyltransferase 3; Sialyltransferase 6 (N-acetyllactosaminide alpha 2,3-sialyltransferase); N-acetyllactosaminide alpha-2,3-sialyltransferase; alpha 2,3-ST 3; ST3GalIII; MRT12; ST3N; Sialyltransferase 6 (N-acetyllacosaminide alpha 2,3-sialyltransferase); Mental Retardation, Non-Syndromic, Autosomal Recessive, 12; Gal Beta-1,3(4) GlcNAc Alpha-2,3 Sialyltransferase; Gal Beta-1,3(4)GlcNAc alpha-2,3 sialyltransferase 3; beta-galactoside alpha-2,3 sialyltransferase 3; alpha 2,3 sialyltransferase III; alpha-2,3 sialyltransferase II; sialyltransferase 6; EC 2.4.99.6; ST3GALII; EIEE15; DEE15

ST3GAL3 is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. ST3GAL3 is normally located in the Golgi apparatus but can be proteolytically processed to a soluble form. ST3GAL3 belongs to glycosyltransferase family 29. ST3GAL3 catalyzes the formation of NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc, and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc sequences found in terminal carbohydrate groups of glycoproteins and glycolipids. The highest activity is towards Gal-beta-1,3-GlcNAc and the lowest towards Gal-beta-1,3-GalNAc.⁹¹
ST3GAL3 is associated with

autosomal recessive non-symdromic cognitive disability, 12
childhood epileptic encephalopathy / epileptic encephalopathy 15
Developmental Disabilities

ST3GAL3 is a candidate gene for ADHD.⁷⁸⁹²⁹³
ST3GAL3 was also identified as an ADHD candidate gene in another large GWAS.¹⁹

1.154. ELAVL4

Other names: ELAV Like RNA Binding Protein 4; PNEM; HUD; ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-Like 4 (Hu Antigen D); ELAV Like Neuron-Specific RNA Binding Protein 4; Paraneoplastic Encephalomyelitis Antigen HuD; ELAV-Like Protein 4; Hu Antigen D; ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-Like 4; Hu Antigen D; HuD

The protein ELAVL4 facilitates mRNA 3’-UTR AU-rich binding activity, poly(A)-binding activity, and pre-mRNA intronic pyrimidine-rich binding activity. ELAVL4 is involved in 3’-UTR-mediated mRNA stabilization, RNA processing, and positive regulation of 3’-UTR-mediated mRNA stabilization. ELAVL4 is thought to be found in the axon, cytoplasm, and dendrites. It appears to be part of the polysomal ribosome and active in the glutamatergic synapse.⁹⁴
ELAVL4

is involved in post-transcriptional regulation of mRNA
is involved in regulation of mRNA stability, alternative splicing and translation
binds to AU-rich element (ARE) sequences in the 3’ untranslated region (UTR) of target mRNAs, including GAP43, VEGF, FOS, CDKN1A, and ACHE mRNA (PubMed:7898713, PubMed:10710437, P
contributes to the differentiation of neuronal progenitor cells, the development of the nervous system, and learning and memory mechanisms
promotes neuronal differentiation of neural stem/progenitor cells in the adult subventricular zone of the hippocampus by binding to and stabilizing SATB1 mRNA
binds and stabilizes MSI1 mRNA in neural stem cells
binds increasingly to ACHE mRNA during neuronal differentiation, thereby stabilizing ACHE mRNA and increasing its expression
protects CDKN1A mRNA from decay by binding to its 3’-UTR
can bind to APP and BACE1 mRNAS and the BACE1AS lncRNA and improve their stabilization
plays a role in the growth of neurites and the establishment and maturation of dendritic branches, contributing to the function of neocortical and hippocampal circuits
stabilizes GAP43 mRNA and protects it from decay during postembryonic development in the brain
promotes GAP43 mRNA stabilization and plays a role in NGF-mediated neurite growth
binds to the long 3’UTR mRNA of BDNF, leading to its stabilization and increased dendritic translation after activation of PKC
increases the translation of BDNF after nerve injury and thus may contribute to nerve regeneration
acts as a stabilizing factor by binding to the 3’UTR of NOVA1 mRNA, thereby increasing its translation and enhancing its functional activity in neuron-specific splicing
stimulates translation of mRNA in a poly(A)- and cap-dependent manner, possibly through association with the EIF4F cap-binding complex
can negatively regulate translation by binding to the 5’UTR of Ins2 mRNA, thereby suppressing its translation
releases Ins2 mRNA upon glucose stimulation, which abolishes translational inhibition
plays a role in the regulation of alternative splicing
may regulate alternative splicing of CALCA pre-mRNA into calcitonin and calcitonin gene-related peptide 1 (CGRP) by competing with the splicing regulator TIAR for binding to U-rich intronic sequences of CALCA pre-mRNA

ELAVL4 is associated with

Lambert-Eaton Myasthenia Syndrome
sensory peripheral neuropathy.

Paralog: ELAVL2.

ELAVL4 is a candidate gene for ADHD.⁷⁸

1.155. NBEAL1

Other names: GeneCards Symbol: NBEAL1; Neurobeachin Like 1; ALS2CR16; ALS2CR17; Amyotrophic Lateral Sclerosis 2 Chromosomal Region Candidate Gene 16 Protein; Amyotrophic Lateral Sclerosis 2 Chromosomal Region Candidate Gene 17 Protein; Amyotrophic Lateral Sclerosis 2 (Juvenile) Chromosomal Region, Candidate 17; Amyotrophic Lateral Sclerosis 2 (Juvenile) Chromosomal Region, Candidate 16; Neurobeachin-Like Protein 1; MGC164581; Neurobeachin-Like 1; A530083I02Rik; Beach

The protein NBEAL1 is thought to activate protein kinase binding activity and appears to be involved in protein localization. NBEAL1is thought to be active in the cytosol and in the membrane.
NBEAL1 is associated with

Amyotrophic lateral sclerosis 2, juvenile
Serous adenocarcinoma of the ovaries

Paralog: NBEAL2

NBEAL1 is a candidate gene for ADHD.⁷⁸

1.156. FGFR3

Other names: GeneCards Symbol: FGFR3; fibroblast growth factor receptor 3; JTK4; CD333; CEK2; EC 2.7.10.1; FGFR-3; ACH; achondroplasia, thanatophoric dwarfism; fibroblast growth factor receptor 3-S; hydroxyaryl protein kinase; tyrosine kinase JTK4; CD333 antigen; HSFGFR3EX; EC 2.7.10

FGFR3 is a member of the fibroblast growth factor receptor (FGFR) family. A representative full-length protein consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors and initiates a cascade of downstream signals that ultimately influence mitogenesis and differentiation.
Fibroblast growth factors (FGFs) are mitogenic signaling molecules involved in angiogenesis, wound healing, cell migration, neuronal growth, and embryonic development. FGF receptors (FGFRs) are transmembrane catalytic receptors with intracellular tyrosine kinase activity.
FGFR3 binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance.
FGFR3 is a tyrosine protein kinase that functions as a cell surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in regulating chondrocyte differentiation, proliferation and apoptosis and is required for normal skeletal development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to activation of multiple signaling cascades. Activation of PLCG1 leads to production of the cellular signaling molecules diacylglycerol and inositol-1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1, and SOS1 and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1, and the MAP kinase signaling pathway, as well as the AKT1 signaling pathway.
Plays a role in the regulation of vitamin D metabolism.
Mutations that lead to constitutive kinase activation or impair normal maturation, internalization, and degradation of FGFR3 result in impaired signal transduction. Overexpressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A, and STAT5B. Secreted isoform 3 retains its ability to bind FGF1 and FGF2 and therefore may impair FGF signaling.⁹⁵
FGFR3 is associated with

Craniosynostosis
different types of skeletal dysplasias.
- Achondroplasia
- Hypochondroplasia

Paralog: FGFR2

FGFR3 is a candidate gene for ADHD.⁷⁸

1.157. ACAD11, Acyl-CoA Dehydrogenase Family Member 11

Other names: Acyl-Coenzyme A Dehydrogenase Family, Member 11; FLJ12592; ACAD-11; Acyl-CoA Dehydrogenase Family, Member 11; EC 1.3.8.-

The protein ACAD11 is an acyl-CoA dehydrogenase enzyme with a preference for carbon chain lengths between 20 and 26. Naturally occurring read-through transcription occurs between the upstream gene NPHP3 (nephronophthisis 3 (adolescent)) and this gene. ACAD11 shows maximal activity toward saturated C22-CoA. ACAD11 is likely involved in beta-oxidation and energy production, but may also play a role in the metabolism of specific fatty acids to control the fatty acid composition of cellular lipids in the brain.⁹⁶
ACAD11 is associated with

Developmental Disabilities
epileptic encephalopathy 44
benign secondary hypertension

Paralog: ACAD10

ACAD11 is a candidate gene for ADHD.⁷⁸

1.158. CNPY2

Other names: Canopy FGF Signaling Regulator 2; ZSIG9; Transmembrane Protein 4; HP10390; TMEM4; MIR-Interacting Saposin-Like Protein; Putative Secreted Protein Zsig9; Protein Canopy Homolog 2; MSAP; Canopy 2 Homolog (Zebrafish)

The protein CNPY2 is thought to be active in the endoplasmic reticulum. CNPY2 is a positive regulator of neurite growth by stabilizing myosin regulatory light chain (MRLC). It prevents MIR-mediated ubiquitination of MRLC and its subsequent proteasomal degradation.⁹⁷
CNPY2 is associated with

Fanconi anemia, complementation group C
Craniosynostosis

Paralog: ENSG00000144785.

CNPY2 is a candidate gene for ADHD.⁷⁸

1.159. PACC1, TMEM206

Other names: PACC1; Proton Activated Chloride Channel; PAC; Transmembrane Protein 206; C1orf75; TMEM206; PAORAC; ASOR; Proton-Activated Outwardly Rectifying Anion Channel; Acid-Sensitive Outwardly-Rectifying Anion Channel; Acid-Sensitive Outwardly Rectifying Channel; Proton-Activated Chloride Channel; FLJ10874; HTMEM206; HPAC; Chromosome 1 Open Reading Frame 75

The protein PACC1 enables the activity of the pH-gated chloride channel. PACC1 is involved in chloride transport. PACC1 is an integral component of the plasma membrane. PACC1 is a proton-activated chloride channel that mediates the import of chloride ions in response to an extracellular acidic pH. PACC1 is involved in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling.

PACC1 or TMEM206 is a candidate gene for ADHD.⁷⁸

1.160. BST1, Bone Marrow Stromal Cell Antigen 1

Other names: ADP-ribosyl cyclase 2; CD157; BST-1; ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2; Bone Marrow Stromal Antigen 1; Cyclic ADP-ribose hydrolase 2; NAD(+) nucleosidase 2; CADPr hydrolase 2; CD157 antigen; EC 3.2.2.6

The protein BST1 is a stromal cell-derived glycosylphosphatidylinositol-anchored molecule that promotes pre-B cell growth. The deduced amino acid sequence has 33% similarity to CD38. Expression of BST1 is increased in bone marrow stromal cell lines from patients with rheumatoid arthritis. The polyclonal B-cell abnormalities in rheumatoid arthritis can be attributed, at least in part, to the overexpression of BST1 in the stromal cell population.⁹⁸
BST1 is associated with

Paroxysmal nocturnal hemoglobinuria
Hemoglobinuria

Paralog: CD38.

UniProtKB/Swiss-Prot summary for BST1 gene
Synthesizes the messengers cyclic ADP-ribose and nicotinate adenine dinucleotide phosphate, the former being a messenger that triggers the release of calcium from intracellular stores. May be involved in the growth of pre-B cells. BST1_HUMAN,Q10588

BST1 is a candidate gene for ADHD.⁷⁸

1.161. RASSF4, Ras Association Domain Family Member 4

Other names: AD037; Ras Association (RalGDS/AF-6) Domain Family Member 4; Ras Association Domain-Containing Protein 4; MGC44914; Ras Association (RalGDS/AF-6) Domain Family 4; Ras Association Domain Family 4; Tumor Suppressor RASSF4

However, the protein RASSF4 may play a role in tumor suppression. Its related pathways include malignant pleural mesothelioma. RASSF4 may act as a KRAS effector protein and promote apoptosis and ell cycle arrest.⁹⁹

Paralog: RASSF2

RASSF4 is a candidate gene for ADHD.⁷⁸

1.163. RAPGEF5, Rap Guanine Nucleotide Exchange Factor 5

Other names: MR-GEF; GFR; KIAA0277; Rap Guanine Nucleotide Exchange Factor (GEF) 5; Guanine Nucleotide Exchange Factor For Rap1; M-Ras-Regulated Rap GEF; M-Ras-Regulated GEF; Related To Epac; MRGEF; REPAC; Repac

Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-gated switches that switch between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs) such as the protein RAPGEF5 serve as RAS activators by promoting the acquisition of GTP to maintain the active GTP-bound state and are the central link between cell surface receptors and RAS activation. The protein RAPGEF5 is a guanine nucleotide exchange factor (GEF) for RAP1A, RAP2A, and MRAS/M-Ras-GTP. Its association with MRAS inhibits the activation of Rap1.¹⁰⁰
RAPGEF5 is associated with

Familial Isolated Hypoparathyroidism

Paralog: RAPGEF4

RAPGEF5 is a candidate gene for ADHD.⁷⁸

1.164. MVP, Major Vault Protein

Other names: LRP; Lung Resistance-Related Protein; VAULT1; Testicular Secretory Protein Li 30

The protein MVP is the main component of the Vault complex. Vault are ribonucleoprotein structures with multiple subunits that may be involved in nucleo-cytoplasmic transport. Vaults are multi-subunit structures that may serve as scaffolds for proteins involved in signal transduction. Vaults may also play a role in nucleo-cytoplasmic transport. MVP may play a role in several cellular processes by regulating MAP kinase, JAK/STAT, and phosphoinositide 3-kinase/Akt signaling pathways. MVP reduces IFNG-mediated STAT1 signaling and subsequent activation of JAK. MVP downregulates SRC activity and signaling through MAP kinases. MVP also plays a role in multidrug resistance. Expression of this gene may be a prognostic marker for various cancers.¹⁰¹
MVP is associated with

Convulsions, familial infantile, with paroxysmal choreoathetosis
therapy-related acute myeloid leukemia
myelodysplastic syndrome

MVP is a candidate gene for ADHD.⁷⁸

1.165. RPS20, Ribosomal Protein S20

Other names: US10; S20; Small Ribosomal Subunit Protein US10; 40S Ribosomal Protein S20

Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together, these subunits consist of 4 RNA species and about 80 structurally distinct proteins.
The ribosomal protein RPS20 is a component of the 40S subunit. RPS20 belongs to the S10P family of ribosomal proteins. It is located in the cytoplasm. This gene is transcribed together with the gene for the small nucleolar RNA U54, which is located in its second intron. As is typical for genes encoding ribosomal proteins, there are several processed pseudogenes of this gene distributed throughout the genome.¹⁰²
RPS20 is associated with:

Diamond-Blackfan anemia
Familial colorectal cancer type X

RPS20 is a candidate gene for ADHD.⁷⁸

1.166. RASGRP4, RAS Guanyl Releasing Protein 4

Other names: RAS guanyl releasing protein 4; guanyl nucleotide releasing protein 4

The protein RASGRP4 belongs to the Ras guanine nucleotide exchange factor family, Ras guanyl nucleotide releasing protein (RasGRP). It contains a Ras exchange motif, a diacylglycerol-binding domain, and two calcium-binding EF hands. RASGRP4 activates H-Ras in vitro in a cation-dependent manner. RASGRP4 functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor that activates Ras by exchanging bound GDP for GTP. RASGRP4 may have a function in mast cell differentiation. It has been found that expression of this protein in myeloid cell lines correlates with increased levels of activated RAS protein and that RAS activation can be greatly enhanced by phorbol ester treatment, suggesting a role for this protein in cell signaling pathways regulated by diacylglycerol. Studies in a mast cell leukemia cell line expressing substantial amounts of abnormal transcripts of this gene suggest that this gene may play an important role in the final stages of mast cell development. Several transcript variants encoding different isoforms have been found for this gene.¹⁰³
RASGRP4 is associated with

Mast cell leukemia
Mastocytosis

Paralog: RASGRP1

RASGRP4 is a candidate gene for ADHD.⁷⁸

1.167. MAP1A, Microtubule-associated protein 1A

Other names: MAP1L; Microtubule-Associated Protein 1A; Proliferation-Related Protein P80; MAP-1A; EC 2.7.2.8; EC 6.3.4.5; MTAP1A

The protein MAP1A belongs to the microtubule associated protein family. MAP1A is a structural protein involved in filamentous cross-bridging between microtubules and other skeletal elements. MAP1A is a precursor polypeptide that presumably undergoes proteolytic processing to form the final heavy chain of MAP1A and the light chain of LC2. Expression of this gene occurs almost exclusively in the brain. Studies of the rat microtubule-associated protein 1A gene suggest a role in early events of spinal cord development.¹⁰⁴
MAP1A is associated with

Granulomatous disease, chronic, autosomal recessive, 3
Woodhouse-Sakati syndrome

Paralog: MAP1B.

MAP1A is a candidate gene for ADHD.¹⁰⁵

1.168. FBXO25, F-BOX ONLY PROTEIN 25

Other names: FBX25; F-Box Only Protein 25; F-Box Protein Fbx25

OMIM: FBXO25, F-BOX ONLY PROTEIN 25

FBXO25 is a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins form one of the four subunits of the ubiquitin-protein ligase complex called SCF (SKP1-Cullin-F-Box), which causes phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws that contain WD-40 domains, Fbls that contain leucine-rich repeats, and Fbxs that contain either different protein-protein interaction modules or no discernible motifs. The protein encoded by this gene belongs to the Fbxs class. FBXO25 is a substrate recognition component of the SCF (SKP1-CUL1-F-box protein) type E3 ubiquitin ligase complex. FBXO25 may play a role in the accumulation of the expanded polyglutamine (polyQ) protein huntingtin (HTT)¹⁰⁶

Paralog: FBXO32

Overexpression of FBXO25 could potentially correlate with hyperactivity.¹⁰⁷

1.169. TRAPPC9, TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 9

Other names: NIBP; KIAA1882; IKBKBBP; TRS120; MRT13; T1; Trafficking Protein Particle Complex 9; NIK- And IKBKB-Binding Protein; Tularik Gene 1 Protein; TRAPP 120 KDa Subunit; NIK And IKK-Beta Binding Protein; IKK2 Binding Protein; Tularik Gene; IBP

OMIM: TRAPPC9, TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 9

The protein TRAPPC9 likely plays a role in NF-kappa B signaling. Mutations in this gene have been associated with autosomal recessive cognitive disability. TRAPPC9 functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. TRAPPC9 may play a role in neuronal cell differentiation. TRAPPC9 may play a role in vesicular transport from the endoplasmic reticulum to the Golgi.¹⁰⁸
TRAPPC9 is associated with

Intellectual development disorder, autosomal recessive 13
Intellectual Disability-Obesity-Brain Malformations-Facial Dysmorphism Syndrome

TRAPPC9 is a candidate gene for ADHD.⁹²

1.170. MEF2C, MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C

Other names: Myocyte Enhancer Factor 2C; Myocyte-Specific Enhancer Factor 2C; MADS Box Transcription Enhancer Factor 2, Polypeptide C; C5DELq14.3; DEL5q14.3; NEDHSIL

OMIM: MEF2C, MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C

This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family that plays a role in myogenesis. The protein MEF2C has both trans-activating and DNA-binding activities. MEF2C may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disabilities, stereotypic movements, epilepsy, and cerebral malformations. MEF2C is a transcriptional activator that specifically binds to the MEF2 element in the regulatory regions of many muscle-specific genes. MEF2C controls cardiac morphogenesis and myogenesis and is involved in vascular development. MEF2C enhances transcriptional activation mediated by SOX18. MEF2C plays an essential role in hippocampus-dependent learning and memory by suppressing the number of excitatory synapses, thereby regulating basal and evoked synaptic transmission. MEF2C is critical for normal neuronal development, distribution, and electrical activity in the neocortex. MEF2C is required for proper development of megakaryocytes and platelets and for B lymphocyte formation in the bone marrow. MEF2C is required for B cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T cell-dependent antigens, and for normal germinal center B cell induction. MEF2C may also be involved in neurogenesis and cortical architecture development.¹⁰⁹
MEF2C is associated with

Neurodevelopmental disorder with hypotonia, stereotyped hand movements, and impaired speech
Autism Spectrum Disorder

Paralog: MEF2A

MEF2C is a candidate gene for ADHD.⁹²

1.171. TNRC6B, TRINUCLEOTIDE REPEAT-CONTAINING GENE 6B

Other names: KIAA1093; Trinucleotide Repeat-Containing Gene 6B Protein; Trinucleotide Repeat Containing 6B; GDSBA

OMIM: TNRC6B, TRINUCLEOTIDE REPEAT-CONTAINING GENE 6B

The protein TNRC6B enables RNA-binding activity. TNRC6B is involved in the regulation of gene expression and is thought to be found in the cytosol as well as active in the P-body and nucleoplasm. TNRC6B plays a role in RNA-mediated gene silencing by both micro RNAs (miRNAs) and short interfering RNAs (siRNAs). TNRC6B is required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by Argonaute family proteins. As a scaffold protein, it associates with Argonaute proteins bound to partially complementary mRNAs and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.¹¹⁰
TNRC6B is associated with

Global developmental delay with speech and behavioral abnormalities
Non-specific syndromic intellectual disability
subserosal uterine fibroid
Uterine fibroid

Paralog: TNRC6A

TNRC6B is a candidate gene for ADHD.¹¹¹

1.172. 22Q11.2

Other names: DEL22Q11.2; Chromosome 22q11.2 Deletion Syndrome, Distal; C22DELq11.2; C22DDELS

DEL22Q11.2 (chromosome 22q11.2 deletion syndrome, distal) is a genetic locus.¹¹²
DEL22Q11.2 is associated with

Chromosome 22Q11.2 Deletion syndrome, distal
Corneal staphyloma.

Individuals with 22q11.2 deletion syndrome (DS) are at increased risk for comorbid mental disorders such as ADHD, schizophrenia, depression, or intellectual disability.¹¹³

1.173. EPHA5, EPH receptor A5

Other names: TYRO4; EHK1; CEK7; HEK7; Ephrin Type-A Receptor 5; EPH Homology Kinase 1; Brain-Specific Kinase; EPH-Like Kinase 7; EC 2.7.10.1; EHK-1; Hek7; EK7; Epididymis Secretory Sperm Binding Protein; Tyrosine-Protein Kinase Receptor EHK-1; Receptor Protein-Tyrosine Kinase HEK7; EC 2.7.10; EphA5; BSK

EPHA5 belongs to the ephrin receptor subfamily of the protein tyrosine kinase family. EPH and EPH-related receptors are involved in mediating developmental events, particularly in the nervous system. The EPH subfamily receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and two fibronectin type III repeats. Ephrin receptors are divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin A and ephrin B ligands. EPHA5 is a receptor tyrosine kinase that promiscuously binds GPI-anchored ephrin-A family ligands located on adjacent cells, resulting in contact-dependent bidirectional signal transduction into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling, while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin A ligands, EFNA5 is most likely the cognate/functional ligand for EPHA5. It functions as an axon guidance molecule during development and may be involved in the development of the retinotectal, entorhino-hippocampal, and hippocamposeptal pathways. Together with EFNA5, it also plays a role in synaptic plasticity in the adult brain by regulating synaptogenesis. In addition to its function in the nervous system, the interaction of EPHA5 with EFNA5 mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion.¹¹⁴
EPHA5 is associated with

Liver Congenital Amaurosis 17
Lung Cancer Susceptibility 3

Paralog: EPHA3

One study found EPHA5 (variant rs4860671) to be one of 96 ADHD candidate genes.⁵²

1.174. RIMS1, Regulating Synaptic Membrane Exocytosis 1

Other names: RIM1; KIAA0340; RAB3IP2; RIM; Regulating Synaptic Membrane Exocytosis Protein 1; Rab-3-Interacting Protein 2; CORD7; Rab-3-Interacting Molecule 1; Rab3-Interacting Molecule 1; RAB3 Interacting Protein 2; RAB3-Interacting Protein 2; Rab3-Interacting Molecule 2; RIM 1

The protein RIMS1 is a member of the RAS gene superfamily that regulates exocytosis of synaptic vesicles. RIMS1 also plays a role as an active site scaffold protein in the regulation of voltage-gated calcium channels during neurotransmitter and insulin release. Mutations suggest a cognitive role. RIMS1 is essential for maintaining the normal probability of neurotransmitter release and for regulating release during short-term synaptic plasticity. RIMS1 plays a role in dendrite formation by melanocytes¹¹⁵
RIMS1 is associated with

Cone-Rod Dystrophy 7
Gyrate Atrophy Of Choroid And Retina

Paralog: RIMS2.

One study found RIMS1 (variant rs4707940) as one of 96 ADHD candidate genes.⁵²

1.175. NRG3, Neuregulin 3

Other names: Pro-Neuregulin-3, Membrane-Bound Isoform 3; Pro-NRG3; Neuregulin-3-Like Polypeptide; HRG3

NRG3 is a member of the neuregulin gene family. This gene family encodes ligands for the transmembrane tyrosine kinase receptors ERBB3 and ERBB4 - members of the epidermal growth factor receptor family. Ligand binding activates intracellular signaling cascades and induction of cellular responses such as proliferation, migration, differentiation and survival or apoptosis. NRG3 activates tyrosine phosphorylation of its cognate receptor ERBB4 and presumably influences neuroblast proliferation, migration, and differentiation by mediating signaling through ERBB4. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. Could be a survival factor for oligodendrocytes. NRG3 promotes mammary gland differentiation during embryogenesis. Linkage studies have shown this gene to be a susceptibility locus for schizophrenia and schizoaffective disorder.¹¹⁶
NRG3 is associated with

Hirschsprung’s disease 1
schizoaffective disorder
Schizophrenia

Paralog: NRG1

One study found NRG3 (variant rs12244269) as one of 96 ADHD candidate genes.⁵²

1.176. TENM4, Teneurin Transmembrane Protein 4

Other names: Ten-M4; KIAA1302; TEN4; ODZ4; Protein Odd Oz/Ten-M Homolog 4; Tenascin-M4; Teneurin-4; Ten-4; TNM4; Odz, Odd Oz/Ten-M Homolog 4 (Drosophila); Odz, Odd Oz/Ten-M Homolog 4; Doc4; ETM5

The protein TENM4 plays a role in establishing proper neuronal connectivity during development. TENM4 plays a role in the formation of the anterior-posterior axis during gastrulation. TENM4 regulates oligodendrocyte differentiation and cellular process formation and myelination of small diameter axons in the CNS. TENM4 promotes activation of focal adhesion kinase and may function as a cellular signal transducer.¹¹⁷
TENM4 is associated with:

Tremor, Hereditary Essential, 5
Tremor

Paralog: TENM3

One study found TENM4 (variant rs1944959) to be one of 96 ADHD candidate genes.⁵²

1.178. MDGA2, MAM Domain Containing Glycosylphosphatidylinositol Anchor 2

Other names: MAMDC1; MAM Domain-Containing Glycosylphosphatidylinositol Anchor Protein 2; MAM Domain Containing 1; MAM Domain-Containing Protein 1; C14_5286

The protein MDGA2 is thought to be involved in cell-cell interactions: in the regulation of presynapse formation, in the regulation of synaptic membrane adhesion, and in the differentiation of spinal cord motor neurons. MDGA2 is thought to act upstream of or within the neuron migration and pattern specification process and is probably localized in the extracellular region and plasma membrane. MDGA2 is probably active in GABA-ergic synapses and glutamatergic synapses.¹¹⁸
MDGA2 is associated with:

dependent personality disorder
benign epilepsy with centrotemporal spikes

Paralog: MDGA1

One study found MDGA2 (variant rs12232114) to be one of 96 ADHD candidate genes.⁵²

1.179. RBFOX1, RNA Binding Fox-1 Homolog 1

Other names: HRNBP1; A2BP1; FOX-1; RNA Binding Protein, Fox-1 Homolog 1; Hexaribonucleotide Binding Protein 1; RNA Binding Protein Fox-1 Homolog 1; Ataxin 2-Binding Protein 1; Fox-1 Homolog A; FOX1; RNA Binding Protein, Fox-1 Homolog (C. Elegans) 1; Hexaribonucleotide Binding Protein 1; Fox-1-Like RNA Binding Protein 1; Ataxin-2-Binding Protein 1; 2BP1; A2BP

The Fox-1 family of RNA-binding proteins is evolutionarily conserved and regulates tissue-specific alternative splicing in metazoans of tissue-specific exons and of differentially spliced exons during erythropoiesis. Fox-1 recognizes a (U)GCAUG segment in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2, which is the product of the SCA2 gene that causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network.¹¹⁹
RBFOX1 is associated with:

Benign epilepsy with centrotemporal spikes
Colorectal cancer
spinocerebellar ataxia type 2 (SCA2)

Paralog: RBFOX2

One study found RBFOX1 (variant rs9935453) to be one of 96 ADHD candidate genes.⁵²

1.180. LIG4, DNA Ligase 4

Other names: Polydeoxyribonucleotide Synthase [ATP] 4; DNA Ligase IV; Ligase IV, DNA, ATP-Dependent; Polynucleotide Ligase; DNA Repair Enzyme; DNA Joinase; EC 6.5.1.1; Sealase; LIG4S

The protein LIG4 is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. LIG4 is essential for V(D)J recombination and repair of DNA double-strand breaks (DSBs) by non-homologous endjoining (NHEJ). This protein forms a complex with X-ray repair cross complementing protein 4 (XRCC4) and interacts with DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are required for NHEJ.¹²⁰
LIG4 is associated with

Lig4 syndrome
Multiple Myeloma

Paralog: LIG3

One study found LIG4 (variant rs9514807) to be one of 96 ADHD candidate genes.⁵²

1.181. NEDD4L, NEDD4 Like E3 Ubiquitin Protein Ligase

Other names: KIAA0439; NEDD4-2; RSP5; Neural Precursor Cell Expressed, Developmentally Down-Regulated 4-Like, E3 Ubiquitin Protein Ligase; HECT-Type E3 Ubiquitin Transferase NED4L; E3 Ubiquitin-Protein Ligase NEDD4-Like; NEDD4.2; Neural Precursor Cell Expressed, Developmentally Down-Regulated 4-Like; Ubiquitin-Protein Ligase Rsp5; EC 2.3.2.26; EC 2.3.2.36; HNEDD4-2; EC 6.3.2; Nedd4-2; PVNH7; NEDL3

The protein NEDD4L is a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. E3 ubiquitin ligases with HECT domain transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, targeting specific proteins for lysosomal degradation. The encoded protein mediates ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating cell surface expression of the epithelial sodium channel (ENaC). NEDD4L is involved in the regulation of various signaling pathways such as autophagy, innate immunity or DNA repair. NEDD4L inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. NEDD4L reduces autophagy and cell growth by ubiquitinating and decreasing cellular ULK1 or ASCT2 levels. NEDD4L plays a role in melanocyte dendrite formation and regulation of TOR signaling.¹²¹
NEDD4L is associated with

Periventricular nodular heterotopia 7
Periventricular nodular heterotopia
essential hypertension

Paralog: NEDD4

One study found NEDD4L (variant rs1620068) to be one of 96 ADHD candidate genes.⁵²

1.182. BMP2, Bone Morphogenetic Protein 2

Other names: BMP2A; Bone Morphogenetic Protein 2A; SSFSC1; BMP-2A; SSFSC; BMP-2; BDA2

The protein BMP2 is a growth factor and secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors, leading to the recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preprotein is proteolytically processed to form the individual subunits of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Growth factor BMP2 plays an essential role in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis. BMP2 induces cartilage and bone formation. BMP2 initiates the canonical BMP signaling cascade through association with the type I receptor BMPR1A and the type II receptor BMPR2. BMP2 may also act through non-canonical signaling pathways such as the ERK/MAP kinase signaling cascade, which regulates osteoblast differentiation. BMP2 stimulates differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A-ATF4 pathway by stimulating EIF2A phosphorylation, which leads to increased expression of ATF4, which plays a central role in osteoblast differentiation¹²²
BMP2 is associated with

Dwarfism
Facial dysmorphism
Skeletal anomalies with or without cardiac anomalies 1
Brachydactyly, type A2

Paralog: BMP4

One study found BMP2 (variant rs952793) to be one of 96 ADHD candidate genes.⁵²

1.182. FAM19A4, TAFA4, TAFA Chemokine Like Family Member 4

Other names: TAFA-4; Family With Sequence Similarity 19 Member A4, C-C Motif Chemokine Like; Chemokine-Like Protein TAFA-4; Family With Sequence Similarity 19 (Chemokine (C-C Motif)-Like), Member A4

The protein TAFA4 belongs to the TAFA family. These proteins contain conserved cysteine residues at fixed positions and are distantly related to MIP-1alpha, a member of the CC chemokine family. The TAFA proteins are expressed predominantly in specific regions of the brain and are thought to function as brain-specific chemokines or neurokines that act as regulators of immune and neuronal cells. TAFA4 modulates injury-induced and chemical pain hypersensitivity. TAFA4 may chemoattract macrophages, promote phagocytosis, and increase ROS release.¹²³
TAFA4 is associated with

Inflammatory bowel disease 9

Paralog: TAFA2

One study found FAM19A4 (variant rs9871910) to be one of 96 ADHD candidate genes.⁵²

1.183. ATXN8OS, ATXN8 Opposite Strand LncRNA

Other names: NCRNA00003; KLHL1AS; SCA8; ATXN8 Opposite Strand (Non-Protein Coding); Non-Protein Coding RNA 3; Spinocerebellar Ataxia 8; Kelch-Like 1 Antisense; Kelch-Like 1 Antisense (Drosophila); Ataxin 8 Opposite Strand; Putative Protein ATXN8OS; ATXN8 Opposite Strand; NONHSAG013730.2; HSALNG0097806; HSALNG0097807; ATXN8OS

ATXN8OS is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not appear to be protein-coding itself. A TAC/TGC trinucleotide repeat expansion incorporated into this gene transcript but not into the KLHL1 transcript causes spinocerebellar ataxia type 8. Presumably, the expansion disrupts the normal antisense function of this transcript.¹²⁴
ATXN8OS is associated with

spinocerebellar ataxia

One study found ATXN8OS (variant rs2498502) to be one of 96 ADHD candidate genes.⁵²

1.184. PPP1R26-AS1

Other names: PPP1R26 antisense RNA 1; NONHSAG053763.2; HSALNG0075163; HSALNG0075157; PPP1R26-AS1

PPP1R26-AS1 is an RNA gene that belongs to the lncRNA class.¹²⁵

One study found PPP1R26-AS1 (variant rs895192) to be one of 96 ADHD candidate genes.⁵²

1.185. BCR, BCR Activator Of RhoGEF And GTPase

Other names: D22S662; D22S11; BCR1; CML; PHL; ALL; BCR, RhoGEF And GTPase Activating Protein; Breakpoint Cluster Region Protein; Renal Carcinoma Antigen NY-REN-26; Breakpoint Cluster Region; EC 2.7.11.1; BCR/FGFR1 Chimera Protein; FGFR1/BCR Chimera Protein

The protein BCR possesses a unique structure with two opposing regulatory activities toward small GTP-binding proteins:

The C-terminus is a GTPase-activating protein (GAP) domain that stimulates GTP hydrolysis by RAC1, RAC2, and CDC42. It accelerates the intrinsic rate of GTP hydrolysis by RAC1 or CDC42, resulting in down-regulation of the active GTP-bound form. The central Dbl homology (DH) domain functions as a guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA, and RAC1. BCR promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form.
The amino terminus contains intrinsic kinase activity. BCR functions as an important negative regulator of neuronal RAC1 activity, regulates macrophage functions such as CSF1-driven motility and phagocytosis by modulating RAC1 activity, plays an important role as a RHOA-GEF in keratinocytes, and is involved in focal adhesion formation and keratinocyte differentiation.

A reciprocal translocation between chromosomes 22 and 9 results in the Philadelphia chromosome, which is often found in patients with chronic myeloid leukemia. The breakpoint on chromosome 22 for this translocation is within the BCR gene. The translocation results in the formation of a fusion protein encoded by sequences from both BCR and ABL, the gene at the breakpoint of chromosome 9. The unregulated tyrosine kinase activity of BCR-ABL1 contributes to the immortality of leukemic cells. The BCR protein has serine/threonine kinase activity and is a GTPase-activating protein for p21rac and other kinases.¹²⁶
BCR is associated with

Chronic Myeloid Leukemia
Chromosome 8P11 Myeloproliferative syndrome

Paralog: ABR

One study found BCR (variant rs140502) to be one of 96 ADHD candidate genes.⁵²

1.186. ZBTB7C, Zinc Finger And BTB Domain Containing 7C

Other names: ZNF857C; ZBTB36; Affected By Papillomavirus DNA Integration In ME180 Cells Protein 1; Zinc Finger And BTB Domain-Containing Protein 7C; Zinc Finger And BTB Domain-Containing Protein 36; Zinc Finger And BTB Domain Containing 36; Zinc Finger Protein 857C; APM-1; APM1; B230208J24Rik

The protein ZBTB7C is thought to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA-binding activity. ZBTB7C is involved in the negative regulation of cell population proliferation and is thought to be localized in the nucleus. ZBTB7C may be a tumor suppressor gene.¹²⁷
ZBTB7C is associated with

L-2 hydroxyglutaric acid disorder

Paralog: ZBTB16

One study found ZBTB7C (variant rs11662736) as one of 96 ADHD candidate genes.¹²⁸

1.187. TSPAN11, Tetraspanin 11

Other names: Tetraspanin-11; Tspan-11; VSSW1971

The protein TSPAN11 is probably involved in cell migration. It is thought to be an integral component of the membrane and an integral component of the plasma membrane.¹²⁹

Paralog: CD151

One study found TSPAN11 (variant rs11051194) to be one of 96 ADHD candidate genes.⁵²

1.188. GRIP1, Glutamate Receptor Interacting Protein 1

Other names: Glutamate Receptor-Interacting Protein 1; FRASRS3; GRIP-1; GRIP

GRIP1 is a member of the glutamate receptor interacting protein family. GRIP1 is a scaffold protein and binds to a number of transmembrane proteins. GRIP1 mediates their trafficking and membrane organization. GRIP1 may play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as a mediator of trafficking of its binding partners at specific subcellular locations in neurons. Through complex formation with NSG1, GRIA2, and STX12, it controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting.¹³⁰
GRIP1 is associated with

Fraser syndrome 3
Fraser syndrome 1

Paralog: GRIP2

One study found GRIP1 (variant rs4913506) to be one of 96 ADHD candidate genes.⁵²

1.189. PRDM2, PR/SET Domain 2

Other names: MTB-ZF; KMT8; RIZ; Retinoblastoma Protein-Interacting Zinc Finger Protein; MTE-Binding Protein; HUMHOXY1; KMT8A; RIZ1; RIZ2; Retinoblastoma Protein-Binding Zinc Finger Protein; PR Domain Containing 2, With ZNF Domain 2; Zinc Finger DNA-Binding Protein; PR Domain Zinc Finger Protein 2; PR Domain-Containing Protein 2; Lysine N-Methyltransferase 8; GATA-3 Binding Protein G3B; Zinc Finger Protein RIZ; PR Domain 2; GATA-3-Binding Protein G3B; EC 2.1.1.355

PRDM2 is a tumor suppressor gene and belongs to the superfamily of nuclear histone/protein methyltransferases. PRDM2 encodes a zinc finger protein that can bind to the retinoblastoma protein, the estrogen receptor, and the TPA-responsive element (MTE) of the heme oxygenase-1 gene. PRDM2 may play a role in transcriptional regulation during neuronal differentiation and retinoblastoma pathogenesis. PRDM2 could function as a transcriptional activator of the heme oxygenase-1 gene. PRDM2 might be a specific effector of estrogen action. PRDM2 is an S-adenosyl-L-methionine-dependent histone methyltransferase that specifically methylates ‘Lys-9’ of histone H3. PRDM2 can function as a DNA-binding transcription factor. PRDM2 binds to the macrophage-specific TPA-responsive element (MTE) of the HMOX1 gene (heme oxygenase 1) and may act as a transcriptional activator of this gene.¹³¹
PRDM2 is associated with

Retinoblastoma
Dyskeratosis Congenita, Autosomal Dominant 2

Paralog: ZNF287

One study found PRDM2 (variant rs7519796) as one of 96 ADHD candidate genes.⁵²

1.190. LINC00609, Long Intergenic Non-Protein Coding RNA 609

Other names: NONHSAG014722.2; NONHSAG014716.2; HSALNG0100629; LINC00609

LINC00609 is an RNA gene that belongs to the lncRNA class.¹³²

One study found LINC00609 (variant rs1537424) to be one of 96 ADHD candidate genes.⁵²

1.191. NAV1, Neuron Navigator 1

Other names: POMFIL3; Steerin-1; KIAA1151; Pore Membrane And/Or Filament Interacting Like Protein 3; Unc-53 Homolog 1; DKFZp781D0314; FLJ12560; FLJ14203; MGC14961; STEERIN1; Pore Membrane And/Or Filament-Interacting-Like Protein; Neuron Navigator-1; KIAA1213; UNC53H1; Unc53H1

The protene NAV1belongs to the family of neuron navigators and is expressed primarily in the nervous system. The encoded protein contains coiled-coil domains and a conserved AAA domain characteristic of ATPases associated with a variety of cellular activities. NAV1 resembles unc-53, a gene from Caenorhabditis elegans involved in axon guidance. NAV1 is thought to play a role in neuronal development and regeneration.¹³³
NAV1 is associated with

Paramyotonia Congenita Of Von Eulenburg
Paroxysmal Extreme Pain Disorder

Paralog: NAV2

One study found NAV1 (variant rs2078097) to be one of 96 ADHD candidate genes.⁵²

1.195. GIMAP6, GTPase, IMAP Family Member 6

Other names: IAN6; Immune-Associated Nucleotide-Binding Protein 6; GTPase IMAP Family Member 6; FLJ22690; IAN-2; IAN-6; IAN2; Immunity-Associated Nucleotide 2 Protein; Immunity-Associated Nucleotide 6 Protein; Immune Associated Nucleotide 2; Immune Associated Nucleotide 6; HIAN2; HIAN6

The protein GIMAP6 is a member of the GTPase family of immunity-associated proteins (GIMAP). GIMAP proteins contain GTP-binding and coiled-coil motifs and may play a role in regulating cell survival.¹³⁴
GIMAP6 is associated with

Lymphopenia
Lung cancer

Paralog: GIMAP1

One study found GIMAP6 (variant rs1403220) to be one of 96 ADHD candidate genes.⁵²

1.196. LIG4, DNA Ligase 4

Other names: Polydeoxyribonucleotide Synthase [ATP] 4; DNA Ligase IV; Ligase IV, DNA, ATP-Dependent; Polynucleotide Ligase; DNA Repair Enzyme; DNA Joinase; EC 6.5.1.1 4; Sealase; LIG4S

The protein LIG4 is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. LIG4 is essential for V(D)J recombination and repair of DNA double-strand breaks (DSBs) by non-homologous endjoining (NHEJ). LIG4 forms a complex with X-ray repair cross complementing protein 4 (XRCC4) and also interacts with DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are required for NHEJ.¹²⁰
LIG4 is associated with

Lig4 syndrome
Multiple Myeloma

Paralog: LIG3

One study found LIG4 (variant rs9514807) to be one of 96 ADHD candidate genes.⁵²

1.199. CSMD1, CUB And Sushi Multiple Domains 1

Other names: KIAA1890; PPP1R24; Protein Phosphatase 1, Regulatory Subunit 24; CUB And Sushi Domain-Containing Protein 1; CUB And Sushi Multiple Domains Protein 1

The protein CSMD1 is thought to be upstream of or involved in several processes, e.g..

Learning
Memory
Branching of the mammary glands during pregnancy
Development of the reproductive organs
CSMD1 is associated with
Aceruloplasminemia
Schizophrenia

Paralog: CSMD2

UniProtKB/Swiss-Prot Summary for CSMD1 Gen
Potential suppressor of squamous cell carcinoma. ( CSMD1_HUMAN,Q96PZ7 )

One study found CSMD1 (variant rs6559123) to be one of 96 ADHD candidate genes.⁵²

1.202. MDGA2, MAM Domain Containing Glycosylphosphatidylinositol Anchor 2

Other names: MAMDC1; MAM Domain-Containing Glycosylphosphatidylinositol Anchor Protein 2; MAM Domain Containing 1; MAM Domain-Containing Protein 1; 14_5286

The protein MDGA2 is likely to be involved in the

Regulation of the assembly of presynapses
Regulation of synaptic membrane adhesion
Differentiation of motor neurons in the spinal cord.¹¹⁸
MDGA2 is vefmiutably active in the GABA-ergic synapse and the glutamatergic synapse.
MDGA2 is associated with
dependent personality disorder
benign epilepsy with centrotemporal spikes

Paralog: MDGA1

One study found MDGA2 (variant rs12232114) to be one of 96 ADHD candidate genes.⁵²

1.203. TBX3, T-box Transcription Factor 3

Other names: TBX3-ISO; XHL; T-box transcription factor TBX3; T-box protein 3; T-box 3; UMS; Bladder Cancer Related Protein XHL; Ulnar Mammary Syndrome

The protein TBX3 belongs to a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. TBX3 is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of tetrapod forelimbs. TBX3, together with TBX2, is required to maintain cell proliferation in embryonic lung mesenchyme.¹³⁵
TBX3 is associated with

Ulnar Mammary Syndrome
- impaired development of limbs, apocrine glands, teeth, hair and genitals
Holt-Oram syndrome

Paralog: TBX2

One study found TBX3 (variant rs4534630) to be one of 96 ADHD candidate genes.⁵²

1.206. FSCB, Fibrous Sheath CABYR Binding Protein

Other names: C14orf155; Fibrous Sheath CABYR-Binding Protein; DKFZP434F1017; Chromosome 14 Open Reading Frame 155

The protein FSCB activates calcium ion binding and is likely involved in the negative regulation of protein umoylation. FSCB may be involved in the later stages of fibrous envelope biogenesis and spermatozoa capacitation. FSCB inhibits SUMOylation of ROPN1 and ROPN1L.¹³⁶
FSCB is associated with

Transient Tic Disorder
Cataract 8, Multiple Types

One study found FSCB (variant rs1957260) as one of 96 ADHD candidate genes.⁵²

1.207. GAN, Gigaxonin

Other names: KLHL16; GAN1; GIG; Kelch-Like Family Member 16; Kelch-Like Protein 16; Epididymis Secretory Sperm Binding Protein; Giant Axonal Neuropathy (Gigaxonin)

The protein GAN is a member of the cytoskeletal BTB/Kelch (Broad-Complex, Tramtrack, and Bric a brac) repeat family. GAN plays a role in neurofilament architecture and is involved in mediating ubiquitination and degradation of some proteins. GAN controls the degradation of TBCB, MAP1B and MAP1S and is critical for neuron maintenance and survival.¹³⁷
GAN is associated with

Giant Axonal Neuropathy 1, Autosomal Recessive
Axonal Neuropathy

Paralog: KLHL2

One study found GAN (variant rs3809632 as well as variant rs9926795) as one of 96 ADHD candidate genes.⁵²

1.208. FSIP2, Fibrous Sheath Interacting Protein 2

Other names: Fibrous Sheath-Interacting Protein 2; FLJ34780; SPGF34

The protein FSIP2 is associated with the sperm fibrous sheath and plays a role in spermatogenesis. Genes encoding most proteins associated with the fibrous sheath are transcribed only during the postmeiotic period of spermatogenesis. FSIP2 is specific to spermatogenic cells¹³⁸
FSIP2 is associated with

Germ cell tumors in the testis
Spermatogenic Failure 34
Non-Syndromic Male Infertility Due To Sperm Motility Disorder.

One study found FSIP2 (variant rs12998684) to be one of 96 ADHD candidate genes.⁵²

1.209. LPAR1, Lysophosphatidic Acid Receptor 1

Other names: LPA1; Rec.1.3; Mrec1.3; Gpcr26; Edg-2; Vzg-1; EDG2; Endothelial Differentiation, Lysophosphatidic Acid G-Protein-Coupled Receptor, 2; Lysophosphatidic Acid Receptor Edg-2; LPA Receptor 1; LPA-1; Ventricular Zone Gene 1; VZG1

LPAR1 is an integral membrane protein. LPAR1 is required for normal brain development. LPAR1 is required for normal proliferation, survival, and maturation of newly formed neurons in the dentate gyrus in adults. LPAR1 plays a role in pain perception and in the initiation of neuropathic pain.
LPAR1 is a lysophosphatidic acid (LPA) receptor belonging to a group known as EDG receptors. These receptors are members of the G protein-coupled receptor superfamily. EDG receptors are used by LPA for cell signaling and mediate various biological functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. LPAR1 activates RALA; this leads to activation of phospholipase C (PLC) and formation of inositol-1,4,5-trisphosphate. LPAR1 promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction. LPAR1 plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14.¹³⁹
LPAR1 is associated with

Pulmonary Fibrosis
Whooping cough (pertussis)

Paralog: LPAR2

One study found LPAR1 (variant rs9919025) to be one of 96 ADHD candidate genes.⁵²

1.211. NXPE2, Neurexophilin And PC-Esterase Domain Family Member 2

Other names: FAM55B; Family With Sequence Similarity 55, Member B; NXPE Family Member 2; Protein FAM55B; FLJ25224; Neurexophilin And PC-Esterase Domain Family, Member 2

The protein NXPE2 is likely an integral component of the membrane.¹⁴⁰

Paralog: NXPE1

One study found NXPE2 (variant rs4938140) to be one of 96 ADHD candidate genes.⁵²

1.214. WNK1, WNK Lysine Deficient Protein Kinase 1

Other names: PPP1R167; PRKWNK1; HSAN2; HSN2; Protein Phosphatase 1, Regulatory Subunit 167; Serine/Threonine-Protein Kinase WNK1; Protein Kinase With No Lysine 1; Erythrocyte 65 KDa Protein; EC 2.7.11.1; KDP; P65; Prostate-Derived Sterile 20-Like Kinase; Hereditary Sensory Neuropathy, Type II; Serine/Threonine-Protein Kinase WNK1 1; Serine/Threonine-Protein Kinase WNK1 2; Protein Kinase, Lysine Deficient 1; Protein Kinase Lysine-Deficient 1; Kinase Deficient Protein; EC 2.7.11; KIAA0344; HWNK1; PSK

The protein WNK1 is a member of the WNK subfamily of serine/threonine protein kinases. WNK1 may be an important regulator of blood pressure by controlling the transport of sodium and chloride ions. WNK1 plays an important role in regulating electrolyte homeostasis, cell signaling, survival, and proliferation. WNK1 acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters, respectively. WNK1 activates SCNN1A, SCNN1B, SCNN1D, and SGK1. WNK1 controls sodium and chloride ion transport by inhibiting the activity of WNK4, either by phosphorylation of the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter SLC12A3 by phosphorylation. WNK1 may also play a role in actin cytoskeleton reorganization. WNK1 phosphorylates NEDD4L. WNK1 acts as a scaffold to inhibit SLC4A4, SLC26A6, and CFTR activities and surface expression. WNK1 recruits STK39, which mediates inhibition.
Isoform 3 is a dominant-negative regulator of the longer isoform 1. Isoform 3 has no kinase activity, does not directly inhibit WNK4, and has no direct effect on sodium and chloride ion transport. Isoform 3 indirectly regulates sodium-chloride cotransporter activity by inhibiting isoform 1, associating with isoform 1, and attenuating its kinase activity. In the kidney, isoform 3 may play an important role in regulating sodium and potassium balance.¹⁴¹
WNK1 is associated with

Neuropathy, hereditary sensory and autonomic, type Iia
Pseudohypoaldosteronism, type Iic

Paralog: WNK2

One study found WNK1 (variant rs7295704) to be one of 96 ADHD candidate genes.⁵²

1.197. LOC101927967, Uncharacterized LOC101927967

Other names: AITD3; TGN; Tg

The protein thyroglobulin (Tg) is a glycoprotein homodimer produced primarily by the thyroid gland. It serves as a substrate for the synthesis of thyroxine and triiodothyronine, and for the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to the site of iodination and subsequent thyroxine biosynthesis in the follicular lumen. TG acts as a substrate for the production of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3). Synthesis of T3 and T4 involves iodination of selected tyrosine residues of TG/thyroglobulin, followed by their oxidative coupling in the lumen of the thyroid follicle. After reinternalization of TG and lysosomal-mediated proteolysis, T3 and T4 are released from the polypeptide scaffold, leading to their secretion into the bloodstream. One dimer generates 7 thyroid hormone molecules.¹⁴²
TG is associated with

Thyroid dyshormonogenesis 3
autoimmune thyroid disease 3
Susceptibility to autoimmune thyroid diseases (AITD) such as Graves’ disease and Hashimoto’s thyroiditis

Paralog: BCHE

One study found TG (variant rs61744749) to be one of 96 ADHD candidate genes.⁵²

1.219. MEP1A, Meprin A Subunit Alpha

Other names: PABA peptide hydrolase; PPHA; N-benzoyl-L-tyrosyl-P-amino-benzoic acid hydrolase subunit alpha; Meprin A, alpha (PABA peptide hydrolase); endopeptidase-2; EC 3.4.24.18; PPH alpha; BA268F1.1 (Meprin A alpha (PABA peptide hydrolase)); EC 3.4.24

The protein MEP1A probably enables metalloendopeptidase activity. MEP1A is probably involved in proteolysis. MEP1A is located in the extracellular exosome and is part of the Meprin-A complex.
MEP1A is associated with

Colorado tick fever
Anisakiasis

Paralog: MEP1B

One study found MEP1A (variant rs7760667) to be one of 96 ADHD candidate genes.⁵²

1.220. ZMYM4, Zinc Finger MYM-Type Containing 4

Other names: Zinc Finger Protein 262; KIAA0425; ZNF198L3; ZNF262; MYM; Zinc Finger MYM-Type Protein 4; Cell Death Inhibiting RNA; Zinc Finger, MYM-Type 4; CDIR

The protein ZMYM4 probably facilitates DNA binding activity. ZMYM4 is involved in the organization of the cytoskeleton and the regulation of cell morphogenesis.¹⁴³

Paralog: ZMYM6.

One study found ZMYM4 (variant rs3768336) to be one of 96 ADHD candidate genes.⁵²

1.221. DIAPH3, Diaphanous Related Formin 3

Other names: DRF3; NSDAN; AN; Protein Diaphanous Homolog 3; FLJ34705; AUNA1; MDia2; Auditory Neuropathy, Autosomal Dominant; Diaphanous (Drosophila, Homolog) 3; Diaphanous Homolog 3 (Drosophila); Diaphanous-Related Formin-3; Diaphanous Homolog 3; Diap3; DIAP3; DIA2

The protein DIAPH3 is a member of the diaphanous subfamily of the formin family. Members of this family are involved in actin remodeling and regulate cell movement and adhesion. DIAPH3 is an actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. DIAPH3 is required for cytokinesis, stress fiber formation, and transcriptional activation of serum response factor. DIAPH3 binds to the GTP-bound form of Rho and to profilin. DIAPH3 acts in a Rho-dependent manner to recruit profilin to the membrane where it promotes actin polymerization. DFR proteins couple Rho and Src tyrosine kinase during signal transduction and regulation of actin dynamics. DIAPH3 also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization in the nucleus to drive serum-dependent SRF-MRTFA activity.¹⁴⁴
DIAPH3 is associated with

Auditory Neuropathy, Autosomal Dominant 1
Autosomal Dominant Non-Syndromic Sensorineural Deafness Type Dfna

Paralog: DIAPH2

One study found DIAPH3 (variant rs2321867) to be one of 96 ADHD candidate genes.⁵²

1.222. SP140L, SP140 Nuclear Body Protein Like

Other names: Nuclear Body Protein SP140-Like Protein; SP140 Nuclear Body Protein-Like; SP140L-1 Protein; SP140L-2 Protein; SP140L-3 Protein

The SP140L protein likely facilitates DNA-binding transcription factor activity specific for RNA polymerase II. SP140L is likely involved in the regulation of transcription by RNA polymerase II. SP140L is likely found in the nuclear body and is predicted to be active in the nucleus.

Paralog: SP140

One study found SP140L (variant rs11688362 and variant rs6732684) as one of 96 ADHD candidate genes.⁵²

1.223. FAM120A, Family With Sequence Similarity 120A

Other names: OSSA; KIAA0183; C9orf10; Constitutive Coactivator Of PPAR-Gamma-Like Protein 1; Oxidative Stress-Associated Src Activator; Oxidative Stess-Associated Src Activator; Chromosome 9 Open Reading Frame 10; Protein FAM120A; HBVPTPAP

The protein FAM120A enables RNA binding activity. FAM120A is found in the cytosol. FAM120A appears to be involved in mRNA transport in the cytoplasm. FAM120A is a critical component of oxidative stress-induced survival signaling. FAM120A activates src family kinases and functions as a scaffold protein that enables src family kinases to phosphorylate and activate PI3 kinase. FAM120A binds RNA and promotes secretion of IGF-II.¹⁴⁵
FAM120A is associated with gastric cancer by supporting cancer cell survival in environments with various oxidative stresses.
Paralog; FAM120C

One study found FAM120A (variant rs1556416) to be one of 96 ADHD candidate genes.⁵²

1.227. CTNNA3, catenin alpha 3

Other names: VR22; catenin (cadherin-associated protein), alpha 3; alpha T-catenin; catenin alpha-3; MGC26194; cadherin-associated protein; alpha catenin-like protein; alpha T-catenin; ARVD13

The ProteDieses gene encodes a protein belonging to the vinculin/alpha-catenin family. CTNNA3 plays a role in cell-cell adhesion in muscle cells. May be involved in the formation of stretch-resistant cell-cell adhesion complexes.¹⁴⁶
CTNNA3 is associated with

arrhythmogenic right ventricular dysplasia, familial 13
Familial isolated arrhythmogenic ventricular dysplasia, biventricular form

Paralog: CTNNA1

UniProtKB/Swiss-Prot Summary for CTNNA3 Gene
May be involved in the formation of stretch-resistant cell-cell adhesion complexes. ( CTNA3_HUMAN,Q9UI47 )

One study found CTNNA3 (variant rs7094454) to be one of 96 ADHD candidate genes.⁵²

1.228. SULT6B1, Sulfotransferase Family 6B Member 1

Other names: Sulfotransferase Family, Cytosolic, 6B, Member 1; Thyroxine Sulfotransferase; Sulfotransferase 6B1; ST6B1; Sulfotransferase SULT6B1; EC 2.8.2.N2

The protein SULT6B1 probably enables sulfotransferase activity. SULT6B1 is thought to be involved in sulfation and is likely located in the cytosol and
be active in the cytoplasm. Sulfotransferase SULT6B1 uses 3’-phospho-5’-adenylyl sulfate (PAPS) as a sulfonate donor to catalyze the sulfate conjugation of thyroxine. Involved in the metabolism of thyroxine.
SULT6B1 is associated with

partial motor epilepsy

Paralog: SULT1C2

One study found SULT6B1 (variant rs4670667) to be one of 96 ADHD candidate genes.⁵²

Sulfotransferases are also involved in the degradation of dopamine. See the article Dopamine degradation: sulfation by sulfotransferases
To what extent SULT6B1 is involved in dopamine degradation is not known to us.

1.235. IPO8, Importin 8

Other names: RANBP8; RAN binding protein 8; Ran binding protein 8; importin-8; IMP8; Imp8; RanBP8; VISS

IPO8 is a protein. The importin-alpha/beta complex and the GTPase Ran mediate nuclear import of proteins with a classical nuclear localization signal. IPO8 belongs to a class of about 20 potential Ran targets that share a sequence motif with the Ran-binding site of importin-beta. IPO8 binds to the nuclear pore complex and, together with RanGTP and RANBP1, inhibits GAP stimulation of Ran GTPase. IPO8 is involved in nuclear protein import, either as an autonomous nuclear transport receptor or as an adaptor-like protein in association with the importin-beta subunit KPNB1. IPO8 acts autonomously, can serve as a receptor for nuclear localization signals (NLS), and promotes translocation of import substrates through the nuclear pore complex (NPC) by an energy-consuming, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin, the importin/substrate complex dissociates, and importin is re-exported from the nucleus to the cytoplasm, where GTP hydrolysis releases Ran.¹⁴⁷
IPO8 is associated with

Viss Syndrome
Aortic aneurysm

Paralog: IPO7
One study found IPO8 (variant rs16906369) to be one of 96 ADHD candidate genes.⁵²

1.236. TBC1D13, TBC1 Domain Family Member 13 2 3 4 5

Other names: FLJ10743; Epididymis Secretory Sperm Binding Protein; TBC1 Domain Family, Member 13

The protein TBC1D13 probably activates GTPase activity for RAB35. WTBC1D13 is probably involved in the activation of GTPase activity and intracellular protein transport and is likely to be found in the cytosol and membrane. TBC1D13, together with RAB35, may be involved in the regulation of insulin-induced glucose transporter SLC2A4/GLUT4 translocation to the plasma membrane in adipocytes.¹⁴⁸
TBC1D13 is associated with

Apocrine carcinoma of the breast

Paralog: TBC1D16
One study found TBC1D13 (variant rs12235388) to be one of 96 ADHD candidate genes.⁵²

1.240. PCSK6, Proprotein Convertase Subtilisin/Kexin Type 6

Other names: SPC4; Subtilisin-Like Proprotein Convertase 4; Subtilisin/Kexin-Like Protease PACE4; PACE4; Paired Basic Amino Acid Cleaving System 4; Paired Basic Amino Acid Cleaving Enzyme 4; Subtilisin-Like Protease; EC 3.4.21.75’); EC 3.4.21.75; EC 3.4.21.61; EC 3.4.21.-; EC 3.4.21

The protein PCSK6 is a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors transported by regulated or constitutive branches of the secretory pathway. PCSK6 undergoes an initial autocatalytic processing in the ER to generate a heterodimer that leaves the ER and resides in the trans-Golgi network, where a second autocatalytic event occurs and catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine organs, liver, intestine, and brain. PCSK6 is one of the seven basic amino acid-specific members that cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta-related proteins, proalbumin, and von Willebrand factor. PCSK6 is thought to play a role in tumor progression and left-right patterning.
PCSK6 is associated with

Anthrax disease
Melon allergy

Paralog: PCSK5

One study found PCSK6 (variant rs2020951) to be one of 96 ADHD candidate genes.⁵²

1.241. DSC3, Desmocollin 3

Other names: CDHF3; DSC1; DSC2; DSC4; DSC; cadherin family member 3; desmocollin-3; desmocollin-4; HT-CP

DSC3 is a calcium-dependent glycoprotein that belongs to the desmocollin subfamily of the cadherin superfamily. These desmosome family members, along with desmogleins, are found primarily in epithelial cells, where they form the adhesive proteins of the desmosomal cell-cell junction and are required for cell adhesion and desmosome formation. The members of the desmosome family are arranged in two clusters on chromosome 18, which together occupy less than 650 kb.¹⁴⁹
DSC3 is associated with

Hypotrichosis
recurrent skin blisters
Pemphigus
Biomarkers for some cancers

Paralog: DSC2

UniProtKB/Swiss-Prot Summary for DSC3 Gen
Component of intercellular desmosome junctions. Participates in the interaction of plaque proteins and intermediate filaments that mediate cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesion between cells expressing different isoforms. ( DSC3_HUMAN,Q14574 )

Gene Wiki entry for DSC3 gene

One study found DSC3 (variant rs2729396) to be one of 96 ADHD candidate genes.⁵²

1.243. EPHA6, EPH Receptor A6

Other names: Ephrin Type-A Receptor 6; EPH Homology Kinase 2; EPH-Like Kinase 12; EC 2.7.10.1; FLJ35246; EHK-2; HEK12; EHK2; EK12; Ephrin Receptor EphA6; EC 2.7.10; PRO57066; EPA6

The protein EPHA6 likely facilitates transmembrane ephrin receptor activity. EPHA6 is likely involved in axon guidance, positive regulation of kinase activity, and transmembrane receptor protein tyrosine kinase signaling. EPHA6 is located in the nucleoplasm. EPHA6 is a receptor tyrosine kinase that promiscuously binds GPI-anchored ephrin A family ligands located on adjacent cells, resulting in contact-dependent bidirectional signal transduction into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling, while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Eph receptors are the largest family of receptor tyrosine kinases (RTKs) and are divided into two subclasses, EphA and EphB. Eph receptors were originally identified as mediators of axon guidance and are involved in many processes, particularly cancer development and progression.¹⁵⁰
EPHA6 is associated with

oculoauricular syndrome

Paralog: EPHA3

One study found EPHA6 (variant rs2053246) to be one of 96 ADHD candidate genes.⁵²

1.244. PLXNC1, Plexin C1

Other names: VESPR; CD232; Virus-Encoded Semaphorin Protein Receptor; Plexin-C1; Receptor For Virally-Encoded Semaphorin; Receptor For Viral Semaphorin Protein; Plexin (Semaphorin Receptor); CD232 Antigen; PLXN-C1

The protein PLXNC1 is a member of the plexin family. Plexins are transmembrane receptors for semaphorins, a large family of proteins that regulate axon guidance, cell motility and migration, and immune response. PLXNC1 is a receptor for SEMA7A, for smallpox semaphorin A39R, vaccinia virus semaphorin A39R, and for herpesvirus sema protein. Binding of semaphorins triggers cellular responses leading to cytoskeletal restructuring and secretion of IL6 and IL8. PLXNC1 and its ligand regulate melanocyte adhesion, and viral semaphorins may modulate immune responses by binding to this receptor. PLXNC1 may be a tumor suppressor protein for melanoma.¹⁵¹
PLXNC1 is associated with:

Polycystic kidney disease 4 with or without polycystic liver disease
Smallpox

Paralog: PLXND1

One study found PLXNC1 (variant rs10859690) to be one of 96 ADHD candidate genes.⁵²

1.245. FSTL5, Follistatin Like 5

Other names: KIAA1263; Follistatin-Related Protein 5; Follistatin-Like Protein 5; DKFZp566D234; Follistatin-Like 5

The protein FSTL5 probably activates the binding of calcium ions. FSTL5 is thought to be involved in cell differentiation and is located in the extracellular region.¹⁵²
FSTL5 is associated with

Clubfoot
Medulloblastoma

Paralog: FSTL4

One study found FSTL5 (variant rs17504151) to be one of 96 ADHD candidate genes.⁵²

1.246. CYFIP1, Cytoplasmic FMR1 Interacting Protein 1

Other names: P140SRA-1; KIAA0068; SHYC; Cytoplasmic FMRP Interacting Protein 1; Cytoplasmic FMR1-Interacting Protein 1; Specifically Rac1-Associated Protein 1; Selective Hybridizing Clone; P140sra-1; SRA-1; Sra-1; SRA1

The protein CYFIP1 regulates cytoskeleton dynamics and protein translation. CYFIP1 is a component of the WAVE regulatory complex (WRC) that promotes actin polymerization. CYFIP1 also interacts with the synaptic function regulator FMR1 protein and translation initiation factor 4E to inhibit protein translation. CYFIP1 is part of the CYFIP1-EIF4E-FMR1 complex, which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex, this subunit is an adaptor between EIF4E and FMR1. CYFIP1 promotes the translational repression activity of FMR1 in the brain, probably by mediating its association with EIF4E and mRNA. CYFIP1 regulates the formation of membrane ruffles and lamellipodia. CYFIP1 plays a role in axon outgrowth. CYFIP1 binds to F-actin but not to RNA. CYFIP1 is part of the WAVE complex, which regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. CYFIP1 is a regulator of epithelial morphogenesis. As a component of the WAVE1 complex, CYFIP1 is required for endocytic BDNF-NTRK2 transport and signaling from early endosomes. CYFIP1 may act as an invasion suppressor in cancer.¹⁵³
CYFIP1 is associated with

Fragile X syndrome
Angelman Syndrome
A large chromosomal deletion involving this gene correlates with an increased risk of schizophrenia and epilepsy in humans
Decreased expression has been observed in several human cancers
CYFIP1 could inhibit tumor invasion

Paralog: CYFIP2

One study found CYFIP1 (variant rs11632784) as one of 96 candidate genes.⁵²

1.247. TUSC1, Tumor Suppressor Candidate 1

Other names: TSG-9; CCDC89B; Tumor Suppressor Candidate Gene 1 Protein; TSG9

The TUSC1 gene is located in the region of chromosome 9p that harbors tumor suppressor genes important in cancer development. It is an intronless gene.¹⁵⁴
TUSC1 is associated with

Duodenal obstruction
Lung cancer
- TUSC1 is downregulated in non-small cell lung cancer and small cell lung cancer cell lines

One study found TUSC1 (variant rs2498716) to be one of 96 ADHD candidate genes.⁵²

1.248. NOTCH2, Notch Receptor 2

Other names: Notch 2; Neurogenic Locus Notch Homolog Protein 2; HN2; Notch (Drosophila) Homolog 2; Notch Homolog 2 (Drosophila); Notch Homolog 2; HJCYS; AGS2

The protein NOTCH2 is a member of the Notch family. This family of type 1 transmembrane proteins share common structural features such as an extracellular domain consisting of multiple EGF-like repeats and an intracellular domain consisting of several different types of domains. Members of the Notch family play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically neighboring cells. In Drosophilia, the Notch interaction with its cell-bound ligands (Delta, Serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologs of Notch ligands have also been identified in humans. NOTCH2 is cleaved in the trans-Golgi network and presented as a heterodimer at the cell surface. NOTCH2 functions as a receptor for membrane-bound ligands and may play a role in vascular, renal, and liver development. NOTCH2 functions as a receptor for the membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2), and Delta-1 (DLL1) and regulates cell fate determination. Upon ligand activation by the released intracellular Notch domain (NICD), NOTCH2 forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. NOTCH2 influences the implementation of differentiation, proliferation and apoptosis programs. NOTCH2 is involved in bone remodeling and homeostasis. NOTCH2 enhances NFATc1 promoter activity in cooperation with RELA/p65 and positively regulates RANKL-induced osteoclast differentiation. NOTCH2 positively regulates liver cancer cell self-renewal.¹⁵⁵
NOTCH2 is associated with

Alagille syndrome 2
Hajdu-Cheney syndrome

Paralog: NOTCH1

One study found NOTCH2 (variant rs2453044) to be one of 96 ADHD candidate genes.⁵²

1.249. OPRK1, Opioid Receptor Kappa 1

Other names: OPRK; KOR; kappa-type opioid receptor; K-OR-1; KOR-1; opioid receptor, kappa 1; opiate receptor, kappa-1; kappa opioid receptor; KOR1; KOP

The protein OPRK1 is a G-protein-coupled opioid receptor for endogenous alpha-neoendorphins, dynorphins, various synthetic opioids, and for the psychoactive diterpene salvinorin A. OPRK1 has a low affinity for beta-endorphins. OPRK1 plays a role in pain perception and in mediating the hypolocomotor, analgesic, and aversive effects of synthetic opioids.
Ligand binding results in inhibition of adenylate cyclase activity and inhibition of neurotransmitter release. OPRK1 inhibits neurotransmitter release by decreasing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. OPRK1 plays a role in mediating decreased physical activity during synthetic opioid treatment and in regulating salivation in response to synthetic opioids. OPRK1 may be involved in arousal and regulation of autonomic and neuroendocrine functions¹⁵⁶
OPRK1 is associated with

Morphine addiction
Alcohol dependence

Paralog: OPRM1

One study found OPRK1 (variant rs7461467) to be one of 96 ADHD candidate genes.⁵²

1.250. ACAA2, acetyl-CoA acyltransferase 2

Other names: DSAEC; Mitochondrial 3-oxoacyl-coenzyme A thiolase; 3-ketoacyl-CoA thiolase, mitochondrial; Mitochondrial 3-oxoacyl-CoA thiolase; Acetyl-coenzyme A acyltransferase 2; Acyl-CoA hydrolase, mitochondrial; Acetyl-CoA acetyltransferase; EC 2.3.1.16; T1; acetyl-CoA acyltransferase; beta ketothiolase; beta-ketothiolase; EC 2.3.1.9; EC 3.1.2.-; EC 3.1.2.1; EC 3.1.2.2; EC 2.3.1

The protein ACAA2 catalyzes the final step of the mitochondrial fatty acid beta-oxidation spiral, an aerobic process in which fatty acids are degraded to acetyl-CoA. ACAA2 probably catalyzes, using free coenzyme A/CoA, the thiolytic cleavage of medium- to long-chain unbranched 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms. ACAA2 probably also catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA and may be involved in the production of ketone bodies. ACAA2 exhibits hydrolase activity on various fatty acyl-CoAs and thereby may be responsible for the production of acetate in a side reaction to beta-oxidation. ACAA2 inhibits BNIP3-mediated apoptosis and mitochondrial damage. Unlike most mitochondrial matrix proteins, ACAA2 contains a non-cleavable amino-terminal targeting signal.¹⁵⁷
ACAA2 is associated with

Alpha-methylacetoacetic aciduria
Ureteral Transitional Cell Carcinoma

Paralog: ACAT2

One study found ACAA2 (variant rs617619) to be one of 96 ADHD candidate genes.⁵²

1.251. DPH2, Diphthamide Biosynthesis 2

Other names: 2-(3-amino-3-carboxypropyl)Histidine Synthase Subunit 2; DPH2L2; S-Adenosyl-L-Methionine:L-Histidine 3-Amino-3-Carboxypropyltransferase 2; Diphtheria Toxin Resistance Protein 2; DPH2 Homolog; Diptheria Toxin Resistance Protein Required For Diphthamide Biosynthesis-Like 2 (S. Cerevisiae); Diptheria Toxin Resistance Protein Required For Diphthamide Biosynthesis-Like 2; Diphthamide Biosynthesis Protein 2 Homolog-Like 2; Diphthamide Biosynthesis-Like Protein 2; Diphthamide Biosynthesis Protein 2; DPH2 Homolog (S. Cerevisiae); DPH2-Like 2 (S. Cerevisiae); DPH2-Like 2

The DPH2 gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain and thus likely has a function in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue in elongation factor 2 (EF2), which is the target of ADP ribosylation by diphtheria toxin. DPH2 is required for the first step of diphthamide biosynthesis, a posttranslational modification of histidine that occurs in elongation factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue. The reaction is supported by a reduction system that includes DPH3 and an NADH-dependent reductase. DPH2 facilitates the reduction of the catalytic iron-sulfur cluster in the DPH1 subunit.¹⁵⁸
DPH2 is associated with

Diphtheria
Immunodeficiency 24

Related metabolic pathways:

Metabolism of proteins
Gamma carboxylation
Hypine formation
Arylsulfatase activation
2-(3-Amino-3-Carboxypropyl)-Histidine Synthase Activity

Paralog: DPH1

DPH2 was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.252. OCT, ornithine transcarbamylase

Other names: Ornithine Transcarbamylase; OTCase; OTCD; Ornithine Carbamoyltransferase, Mitochondrial; Ornithine Transcarbamylase, Mitochondrial; EC 2.1.3.3; OTC1; Ornithine Transcarbamylase Deficiency; Ornithine Carbamoyltransferase; EC 2.1.3; OCTD

The protein OTC is a mitochondrial matrix enzyme. OCT catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline. The urea cycle provides detoxification of ammonia by converting it to urea for excretion.¹⁵⁹
OTC is associated with

Ornithine transcarbamylase deficiency
Hyperammonemia
Disturbance of the ornithine metabolism

Related metabolic pathways:

Superpathway of L-Citrulline Metabolism
Pyrimidine metabolism
Phospholipid binding
Phosphate-ion binding

Paralog: CAD

Ornithine transcarbamylase deficiency¹⁶⁰ occurs in approximately 1 / 30,000 people and is due to a genetic defect in the OTC gene. Gene mutations with residual enzyme activity also exist, so they may not be diagnosed immediately. Affected individuals develop typical neuropsychological complications such as¹⁶¹

Developmental delay
Learning Disability
mental disability
Attention Deficit/Hyperactivity Disorder
Deficits in the executive function

1.253. KC6, Keratoconus Gene 6

Other names: NONHSAG023745.2; HSALNG0121143; Lnc-RIT2-2

KC6 is an RNA gene and belongs to the lncRNA class.¹⁶²
KC6 is associated with

Keratoconus
Inhalation anthrax

One study found KC6 (variant rs16974432) to be one of 96 ADHD candidate genes.⁵²

1.255. LINC00970, Long Intergenic Non-Protein Coding RNA 970

Other names: NONHSAG003406.2; HSALNG0008302; LINC00970

LINC00970 is an RNA gene that belongs to the lncRNA class.¹⁶³
LINC00970 is associated with

Corneal dystrophy
perceptive deafness
Fuchs’ endothelial dystrophy

One study found LINC00970 (variant rs16861817) to be one of 96 ADHD candidate genes.⁵²

1.257. MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Other names: Methionine Synthase Reductase; CblE; Aquacobalamin Reductase; AqCbl Reductase; MSR; [Methionine Synthase]-Cobalamin Methyltransferase (Cob(II)Alamin Reducing); Methionine Synthase Reductase, Mitochondrial; EC 1.16.1.8

The protein MTRR is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. MTRR is key enzyme of methionine and folate homeostasis responsible for reactivation of methionine synthase (MTR/MS) activity by catalyzing reductive methylation of MTR-bound cob(II)alamine. Since methionine synthesis requires methyl group transfer through a folate donor, the activity of the encoded enzyme is important for folate metabolism and cellular methylation. Cobalamin (vitamin B12) forms a complex with MTR and serves as an intermediate in methyl transfer reactions that cycle between MTR-bound methylcob(III)alamine and MTR-bound cob(I)alamine forms. Occasional oxidative escape of the cob(I)alamine intermediate during the catalytic cycle presumably leads to the inactive cob(II)alamine species. Processing of cobalamin in the cytosol occurs in a multiprotein complex consisting of at least MMACHC, MMADHC, MTRR, and MTR, which may help transport cobalamin safely and efficiently to MTR to produce methionine. MTRR is necessary for the utilization of methyl groups from the folate cycle, affecting transgenerational epigenetic inheritance . MTRR acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamine into apoMTR to form the holoenzyme. MTRR serves as an aquacob(III)alamine reductase by reducing aquacob(III)alamine to cob(II)alamine; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamine to MTR holoenzyme¹⁶⁴
Mutations in this gene can cause homocystinuria-megaloblastic anemia, type cbl E. Alternative splicing of this gene results in multiple transcript variants.
MTRR is associated with

Homocystinuria - megaloblastic anemia, Cble complementation type
Homocystinuria without methylmalonic aciduria

Related metabolic pathways include cobalamin (Cbl, vitamin B12) transport, metabolism, and disease

Paralog: POR

One study found MTRR (variant rs924977) as one of 96 ADHD candidate genes.⁵²

1.258. ADAMDEC1, ADAM Like Decysin 1

Other names: M12.219; A Disintegrin And Metalloproteinase Domain-Like Protein Decysin-1; ADAM-Like Protein Decysin-1; ADAM DEC1; Disintegrin Protease; EC 3.4.24.-; Decysin

ADAMDEC1 is thought to be a secreted protein of the disintegrin metalloproteinase family. Its expression is upregulated during the maturation of dendritic cells. This protein may play an important role in the function of dendritic cells and their interaction with germinal center T cells. ADAMDEC1 may play an important role in the control of immune response and during pregnancy.¹⁶⁵
ADAMDEC1 is associated with

Rosacea

Paralog: ADAM28

One study found ADAMDEC1 (variant rs4872233 and variant rs7012077) as one of 96 ADHD candidate genes.⁵²

1.259. CLIC4, Chloride Intracellular Channel 4

Other names: P64H1; CLIC4L; HuH1; H1; Intracellular Chloride Ion Channel Protein P64H1; Chloride Intracellular Channel Protein 4; DKFZP566G223; Epididymis Secretory Sperm Binding Protein; Chloride Intracellular Channel 4 Like; MTCLIC

The protein is a chloride channel. Chloride channels are a diverse group of proteins that regulate basic cellular processes, including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. CLIC4 is a member of the p64 family. CLIC4 can insert into membranes and form poorly selective ion channels that can also transport chloride ions. Channel activity depends on pH. Membrane insertion appears to be redox-regulated and can only occur under oxidizing conditions. CLIC4 promotes the expression of HRH3 on the cell surface. CLIC4 has alternative cellular functions such as a possible role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. CLIC4 may also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis).CLIC4 is expressed in many tissues and shows an intracellular vesicular pattern in Panc-1 cells (pancreatic cancer cells).¹⁶⁶
CLIC4 is associated with pancreatic cancer.
Related metabolic pathways are

Glucose/energy metabolism
Activation of cAMP-dependent PKA
Paralog: CLIC6

One study found CLIC4 (variant rs2223365) to be one of 96 ADHD candidate genes.⁵²

1.260. SLC13A5, Solute Carrier Family 13 Member 5

Other names: NACT; INDY; Solute Carrier Family 13 (Sodium-Dependent Citrate Transporter), Member 5; Na(+)/Citrate Cotransporter; Sodium-Dependent Dicarboxylate Transporter; Na+-Coupled Citrate Transporter Protein; Sodium-Dependent Citrate Transporter; Sodium-Coupled Citrate Transporter; EIEE25; DEE25; MIndy; NaCT

The protein SLC13A5 belongs to the group of solute carrier family 13 proteins and is a sodium-dependent citrate cotransporter that mediates the entry of citrate into cells. With much lower affinity, other citric acid cycle intermediates such as succinate, fumarate, malate, oxaloacetate, and alpha-ketoglutarate also serve as substrates of SLC13A5. The substrate sensitivity of SLC13A5 is citrate > malate ~ alpha-ketoglutarate > succinate ~ fumarate > oxaloacetate ~ isocitrate.¹⁶⁷
SLC13A5 is associated with

Developmental And Epileptic Encephalopathy 25 With Amelogenesis Imperfecta
Developmental And Epileptic Encephalopathy 25

Related signaling pathways involve the transport of inorganic cations/anions and amino acids/oligopeptides.
Paralog: SLC13A2.

One study found SLC13A5 (variant rs41463346) to be one of 96 ADHD candidate genes.⁵²

1.262. ACSL3, Acyl-CoA synthetase long chain family member 3

Other names: ACS3; PRO2194; FACL3; Fatty-Acid-Coenzyme A Ligase, Long-Chain 3; Long-Chain-Fatty-Acid–CoA Ligase 3; Medium-Chain Acyl-CoA Ligase Acsl3; Long-Chain Acyl-CoA Synthetase 3; Fatty Acid CoA Ligase Acsl3; Arachidonate–CoA Ligase; EC 6.2.1.3 4; LACS 3; LACS3; Lignoceroyl-CoA Synthase; EC 6.2.1.15; EC 6.2.1.2

The protein ACSL3 is an isozyme of the long-chain fatty acid coenzyme A ligase family. Although all isozymes of this family differ in substrate specificity, subcellular localization, and tissue distribution, they convert free long-chain fatty acids into fatty acyl-CoA esters for both synthesis of cellular lipids and degradation by beta-oxidation. Fatty acid coenzyme A ligases thus play a key role in lipid biosynthesis and fatty acid degradation. ACSL3 is required for the incorporation of fatty acids into phosphatidylcholine, the major phospholipid on the surface of VLDL (very low density lipoproteins). ACSL3 has mainly an anabolic role in energy metabolism. ACSL3 mediates hepatic lipogenesis.
ACSL3 is highly expressed in the brain and preferentially uses myristate, arachidonate, and eicosapentaenoate as substrates.¹⁶⁸
ACSL3 is associated with

Intellectual Developmental Disorder, Autosomal Dominant 38
Saethre-Chotzen Syndrome

Related signaling pathways:

Integration of the energy metabolism
Arachidonate biosynthesis III (6-desaturase, mammals)
Protein kinase binding
long-chain fatty acid CoA ligase activity

Paralog: ACSL4

One study found ACSL3 (variant rs10498143) to be one of 96 ADHD candidate genes.⁵²

1.264. METTL8, Methyltransferase 8, Methylcytidine

Other names: TIP; TRNA N(3)-methylcytidine methyltransferase METTL8, Mitochondrial; MRNA N(3)-methylcytidine methyltransferase METTL8; Tension-Induced/Inhibited Protein; Methyltransferase-Like Protein 8; Methyltransferase Like 8; FLJ13984; EC 2.1.1.-

The protein METTL8 enables mRNA methyltransferase activity. METTL8 is involved in mRNA methylation ubd is thought to be found in the cytoplasm and nucleus. METTL8 is a mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN) and tRNA(Thr). The N(3)-methylcytidine methylation modification regulates mitochondrial translational efficiency and is required for respiratory chain activity. N(3)-methylcytidine methylation of mitochondrial tRNA(Ser)(UCN) requires the formation of N(6)-dimethylallyladenosine(37) (i6A37) by TRIT1 as a prerequisite. METTL8 can mediate N(3)-methylcytidine modification of mRNAs¹⁶⁹
METTL8 is associated with

Woodhouse-Sakati syndrome
hepatocellular carcinoma in adults

Related metabolic pathways:

Methyltransferase activity
Histone acetyltransferase activity

Paralog: METTL2A

One study found METTL8 (variant rs17218608) as one of 96 ADHD candidate genes.⁵²

1.265. ZNF777, Zinc Finger Protein 777

Other names: KIAA1285

The protein ZNF777 likely facilitates DNA-binding transcription factor activity, an RNA polymerase II-specific region, and an RNA polymerase II cis-regulatory region with sequence-specific DNA-binding activity. ZNF777 is thought to be involved in the regulation of transcription by RNA polymerase II and is active in the nucleus. ZNF777 may be involved in transcriptional repression and inhibits cell proliferation through CDKN1A/p21 induction via down-regulation of NIBAN1/FAM129A at low cell density.¹⁷⁰
Related metabolic pathway:

Gene expression (transcription)
Nucleic acid binding

Paralog: ZNF398

One study found ZNF777 (variant rs17852167) as one of 96 candidate genes.⁵²

1.266. TFAP2D, Transcription Factor AP-2 Delta

Other names: AP-2delta; TFAP2BL1; Transcription Factor AP-2 Beta (Activating Enhancer-Binding Protein 2 Beta)-Like 1; Transcription Factor AP-2 Delta (Activating Enhancer Binding Protein 2 Delta); Activating Enhancer-Binding Protein 2-Delta; Transcription Factor AP-2-Beta-Like 1; Transcription Factor AP-2-Delta; AP2-Delta; Activating Enhancer Binding Protein 2 Beta-Like 1; AP-2 Like

The protein TFAP2D probably activates

a DNA-binding transcription factor activity
an RNA polymerase II-specific DNA binding activity
an RNA polymerase II transcriptional regulatory region sequence-specific DNA binding activity

TFAP2D is thought to be involved in

Development of anatomical structures
Regulation of the proliferation of cell populations
Regulation of transcription by RNA polymerase II
negative regulation of the apoptotic process of neurons
positive regulation of transcription by RNA polymerase II

TFAP2D interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5’-GCCNNNNGGC-3’ and activate genes involved in a wide range of important biological functions, including proper eye, face, body wall, limb, and neural tube development. They also repress a number of genes, including MCAM/MUC18, C/EBP alpha and MYC.¹⁷¹

TFAP2D is associated with

Char syndrome
Branchiooculofacial syndrome

Related metabolic pathways:

Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors
Gene expression (transcription)

One study found TFAP2D (variant rs78648104) to be one of 96 ADHD candidate genes.⁵²

1.267. OTOR, Otoraplin

Other names: FDP; Fibrocyte-Derived Protein; MIAL1; MIAL; Melanoma Inhibitory Activity-Like Protein

The protein OTOR belongs to the family of melanoma inhibitory activity. OTOR is secreted via the Golgi apparatus and may have a function in cartilage development and maintenance.
OTOR is associated with

Melanomas
Translation cancellation
Numbness

Paralog: MIA

One study found OTOR (variant rs6105651) as one of 96 ADHD candidate genes.⁵²

1.269. EEPD1, Endonuclease/Exonuclease/Phosphatase Family Domain Containing 1

Other names: KIAA1706; endonuclease/exonuclease/phosphatase family domain-containing protein 1; HSPC107

The protein EEPD1 probably enables DNA binding activity and involved in the positive regulation of cholesterol efflux.
EEPD1 anchored in the plasma membrane.¹⁷²
EEPD1 is associated with

Meningitis carcinoma

Related signaling pathways:

Signal transduction
NR1H2- and NR1H3-mediated signal transduction

One study found EEPD1 (variant rs2726059) to be one of 96 ADHD candidate genes.⁵²

1.270. MAD2L1, Mitotic Arrest Deficient 2 Like 1

Other names: MAD2; HSMAD2; MAD2 (Mitotic Arrest Deficient, Yeast, Homolog)-Like 1; Mitotic Spindle Assembly Checkpoint Protein MAD2A; Mitotic Arrest Deficient 2-Like Protein 1; MAD2-Like Protein 1; Mitotic Arrest Deficient, Yeast, Homolog-Like 1; MAD2 Mitotic Arrest Deficient-Like 1; HsMAD2

The protein MAD2L1 is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate.¹⁷³
MAD2L1 iat associated with

Mosaic Variegated Aneuploidy Syndrome 1
Embryoma

Related signaling pathways:

APC-Cdc20-mediated degradation of Nek2A
Cell cycle, mitotic
Protein homodimerization activity
identical protein binding

Paralog: MAD2L2

One study found MAD2L1 (variant rs1553692) as one of 96 ADHD candidate genes.⁵²

1.271. FLRT2, Fibronectin Leucine Rich Transmembrane Protein 2

Other names: Fibronectin-Like Domain-Containing Leucine-Rich Transmembrane Protein 2; Leucine-Rich Repeat Transmembrane Protein FLRT2; KIAA0405

The protein FLRT2 is a member of the fibronectin-leucine-rich transmembrane (FLRT) family of cell adhesion molecules that regulate early embryonic vascular and neural development. FLRT2 functions as both a homophilic cell adhesion molecule and a heterophilic chemorepellent through its interaction with members of the uncoordinated-5 receptor family. Proteolytic removal of the extracellular region controls the migration of neurons in the developing cortex¹⁷⁴

FLRT2 is involved in

Cell-cell adhesion
- on its interactions with ADGRL3 and probably other latrophilins expressed on the surface of neighboring cells
Cell migration
- on its interaction with UNC5D in the migration of cortical neurons during brain development
Axon guidance.
- mediates the collapse of the axon growth cone
- plays a repulsive role in neuron guidance via its interaction with UNC5D and possibly other members of the UNC-5 family. Plays a role in fibroblast growth factor-mediated signaling cascades
Organization of the cardiac basement membrane
- Required for normal organization of the cardiac basement membrane during embryogenesis and for normal embryonic epicardial and cardiac morphogenesis.

Related signaling pathways:

Signal transduction
negative regulation of FGFR1 signaling
Protein macromolecule adaptor activity
chemorepellent activity

Paralog: FLRT3
One study found FLRT2 (variant rs17712565) to be one of 96 ADHD candidate genes.⁵²

1.272. PLD5, Phospholipase D Family Member 5

Other names: Inactive Phosphatidylcholine Hydrolyzing Phospholipase D5; Inactive Choline Phosphatase 5; Inactive Phospholipase D5; Inactive PLD 5; FLJ40773; Phospholipase D Family, Member 5; PLDC; PLDc

The protein PLD5 likely enables catalytic activity and is thought to be an integral component of the membrane.¹⁷⁵
PLD5 is associated with

Nephrotic syndrome, type 7

Paralog: PLD3

One study found PLD5 (variant rs4658830) to be one of 96 ADHD candidate genes.⁵²

1.274. CASC20, Cancer Susceptibility 20

Other names: Cancer Susceptibility Candidate 20; Cancer Susceptibility 20; NONHSAG031223.2; HSALNG0128472; CASC20

CASC20 is an RNA gene that belongs to the lncRNA class.¹⁷⁶

One study found CASC20 (variant rs6038589) to be one of 96 ADHD candidate genes.⁵²

1.276. COBLL1, Cordon-Bleu WH2 Repeat Protein Like 1

Other names: KIAA0977; Cordon-Bleu Protein-Like 1; COBL-Like 1; Cordon-Bleu WH2 Repeat Protein-Like 1; COBLR1

The protein COBLL1 enables cadherin binding activity. COBLL1 is located in the extracellular exosome.¹⁷⁷
COBLL1 is associated with

Macular degeneration, age-related, 10

Related soff metabolism pathways: actin binding

Paralog: COBL

One study found COBLL1 (variant rs139834711) to be one of 96 ADHD candidate genes.⁵²

1.277. PAPOLA, Poly(A) Polymerase Alpha

Other names: PAP; polynucleotide adenylyltransferase alpha; EC 2.7.7.19; PAP alpha; EC 2.7.7

The protein PAPOLA belongs to the family of poly(A) polymerases. PAPOLA is required for the addition of adenosine residues to form the 3’ poly(A) tail of mRNAs, as well as for the endoribonucleolytic cleavage reaction at some polyadenylation sites. PAPOLA can acquire its specificity by interacting with a cleavage and polyadenylation specificity factor (CPSF) at its C-terminus.¹⁷⁸
PAPOLA is associated with

46,Xx Sex Reversal 3
Combat Disorder

Related Signal Paths:

Processing of Capped Intronless Pre-mRNA
Processing of Capped Intron-Containing Pre-mRNA
RNA binding
Manganese-ion bond

Paralog: PAPOLB

One study found PAPOLA (variant rs7160641)as one of 96 candidate genes.⁵²

1.280. KDM4A, Lysine Demethylase 4A

Other names: JHDM3A; KIAA0677; TDRD14A; JMJD2A; JMJD2; JmjC domain-containing histone demethylation protein 3A; Jumonji C domain-containing histone demethylase 3A; [Histone H3]-trimethyl-L-lysine(36) demethylase 4A; [Histone H3]-Trimethyl-L-Lysine(9) Demethylase 4A; Jumonji Domain-Containing Protein 2A; Lysine (K)-Specific Demethylase 4A; Lysine-Specific Demethylase 4A; Jumonji Domain Containing 2A; Tudor Domain Containing 14A; Jumonji Domain Containing 2; EC 1.14.11.66; EC 1.14.11.69; C 1.14.11

The Jumonji domain 2 (JMJD2) family protein KDM4A contains a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This core protein functions as a trimethylation-specific demethylase that converts specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor.KDM4A is a histone demethylase that specifically demethylates ‘Lys-9’ and ‘Lys-36’ residues of histone H3, playing a central role in the histone code. KDM4A does not demethylate histone H3 ‘Lys-4’, H3 ‘Lys-27’, and H4 ‘Lys-20’, but does demethylate trimethylated H3 ‘Lys-9’ and H3 ‘Lys-36’ residues, whereas it has no effect on mono- and dimethylated residues. Demethylation of Lys residues produces formaldehyde and succinate. KDM4A is involved in transcriptional repression of ASCL2- and E2F-responsive promoters by recruiting histone deacetylases and NCOR1, respectively.
[isoform 2]: Critical for muscle differentiation, promotes transcriptional activation of the myog gene by directing the removal of repressive chromatin marks at its promoter. It lacks the N-terminal demethylase domain.¹⁷⁹
KDM4A is associated with

primary hyperoxaluria

Related signaling pathways:

Homology-driven repair
DNA double-strand break reaction
Ubiquitin protein ligase binding
Histone H3 methyl lysine 36 demethylase activity

Paralog: KDM4C

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.281. KDM4A-AS1, KDM4A Antisense RNA 1

Other names: KDM4A Antisense RNA 1; NONHSAG001242.2; HSALNG0003118; KDM4A-AS1

KDM4A-AS1 is an RNA gene that belongs to the lncRNA class.¹⁸⁰

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.282. PTPRF, Protein Tyrosine Phosphatase Receptor Type F

Other names: LAR; Receptor-Type Tyrosine-Protein Phosphatase F; Leukocyte Common Antigen Related; EC 3.1.3.48; Protein Tyrosine Phosphatase, Receptor Type, F Polypeptide; Receptor-Linked Protein-Tyrosine Phosphatase LAR; Leukocyte Antigen-Related Tyrosine Phosphatase; Leukocyte Antigen-Related (LAR) PTP Receptor; LCA Homolog; BNAH2

The protein PTPRF belongs to the family of protein tyrosine phosphatases (PTPs). PTPs are signaling molecules that regulate a variety of cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPRF has an extracellular region, a single transmembrane region, and two tandem intracytoplasmic catalytic domains, making it a receptor-type PTP. The extracellular region contains three Ig-like domains and nine non-Ig-like domains similar to those of the Neural-Cell Adhesion Molecule. PTPRF plays a role in regulating epithelial cell contacts at adhesion sites and in controlling beta-catenin signaling. PTPRF may be a cell adhesion receptor. PTPRFpossesses intrinsic protein tyrosine phosphatase (PTPase) activity and dephosphorylates EPHA2, regulating its activity. The first PTPase domain has enzymatic activity, while the second domain appears to affect the substrate specificity of the first.¹⁸¹
PTPRF is associated with

Aplasia / hypoplasia of breasts / nipples, 2
isolated congenital breast hypoplasia / aplasia
Insulin Resistance
- increased PTPRF expression was detected in insulin-responsive tissues of obese, insulin-resistant individuals

Related signaling pathways:

Unblocking of NMDA receptors
Glutamate binding and activation
Cadherin-mediated cell adhesion
Binding of proteinaceous complexes
Phosphatase activity

Paralog: PTPRD

PTPRD belongs to the same signaling pathway as CREB3, CSMD1, and GAB1, which are involved in neuron differentiation and the dopamine pathway.¹⁸²

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.284. CCDC24, Coiled-Coil Domain Containing 24

Other names: Coiled-Coil Domain-Containing Protein 24; MGC45441

The protein CCDC24 probably acts before or during blastocyst hatching.¹⁸³

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.286. IPO13, Importin 13

Other names: RANBP13; KIAA0724; IMP13; Ran binding protein 13; Importin-13; Ran binding protein 13; Late Gestation Lung; Karyopherin 13; Karyopherin-13; RanBP13; KAP13; Imp13; Kap13; LGL2

The protein IPO13 is a member of the importin-beta family of nuclear transport proteins. IPO13 mediates the import of specific cargo proteins from the cytoplasm into the nucleus and is dependent on the Ras-related nuclear protein GTPase system. IPO13 is also involved in nuclear export of eukaryotic translation initiation factor 1A. IPO13 serves as a receptor for nuclear localization signals (NLS) in cargo substrates. IPO13 presumably mediates the docking of the importin/substrate complex to the nuclear pore complex (NPC) by binding to nucleoporin, whereupon the complex is translocated through the pore by an energy-consuming, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin, the importin/substrate complex dissociates, and importin is re-exported from the nucleus to the cytoplasm, where Ran is released by GTP hydrolysis. The directionality of nuclear import appears to be due to an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. IPO13 mediates nuclear import of UBC9, the RBM8A/MAGOH complex, PAX6, and probably other members of the paired-homeobox family. IPO13 mediates nuclear export of eIF-1A, and cytoplasmic release of eIF-1A is triggered by loading of import substrates onto IPO13.¹⁸⁴
IPO13 is associated with:

Partington syndrome
Corpus Callosum, Agenesis of, With Abnormal Genitalia
- Agenesis of the corpus callosum, severe mental retardation, seizures, and spasticity. Males are severely affected, while females may be unaffected or have a milder phenotype.

Related signal paths are:

Binding of small GTPases

Paralog: TNPO3

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.307. NT5DC1

One study found evidence that common signal transduction molecules (such as NT5DC1, PSD, SEC23IP, and ZCCHC4) play an important role in the etiology of ADHD. Therole of cellular communication appears to be a potential core component in the development of ADHD in both adults and children.¹⁸⁵

1.308. PSD

1.309. SEC23IP

1.310. ZCCHC4

1.311. SHANK2, SH3 And Multiple Ankyrin Repeat Domains 2

Other names; CTTNBP1; ProSAP1; SPANK-3; CORTBP1; SHANK; SH3 And Multiple Ankyrin Repeat Domains Protein; Cortactin-Binding Protein 1; Proline-Rich Synapse Associated Protein 1; Proline-Rich Synapse-Associated Protein 1; Cortactin SH3 Domain-Binding Protein; GKAP/SAPAP Interacting Protein; Cortactin Binding Protein 1; KIAA1022; PROSAP1; CortBP1; AUTS17; Shank2

SHANK2 belongs to the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats and an SH3 domain. SHANK2 contains a PDZ domain, a consensus sequence for cortactin-SH3 domain-binding peptides, and a sterile alpha motif. Alternative splicing detected in Shank genes has been proposed as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. SHANK2 appears to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that links postsynaptic membrane receptors, including NMDA receptors and metabotropic glutamate receptors, and the actin-based cytoskeleton. SHANK2 may play a role in the structural and functional organization of the dendritic spine and synaptic junction
SHANK2 is associated with

Susceptibility to autism spectrum disorders
Autism 17
Autism Spectrum Disorder

Related Signal Paths:

Protein-protein interactions at synapses
Regulation of CFTR activity (norm and CF)
SH3 domain binding
synaptic receptor-adaptor activity

Paralog: SHANK1

SHANK2 is thought to be involved in AD(HJ)S.¹⁸⁶¹⁸⁷
Overexpression of the extrasynaptic SHANK2A(R462X) variant showed ADHD-like behavior.¹⁸⁸

1.315. KDM6B, Lysine Demethylase 6B

KDM6B showed the highest potential as a risk gene for ADHD and ASD in one study.¹⁸⁹

1.316. ZNF148

A de novo truncated ZNF148 variant has been observed to cause ASD, ADHD, and intellectual disability.¹⁹⁰

Non-protein coding genes: RNA genes

1.87. FEZF1-AS1, FEZF1 antisense RNA 1 (chromosome 7q31.32)

FEZF1-AS1 is not a protein gene but an RNA gene of the lncRNA class. FEZF1-AS1 is associated with the following diseases:

ductal adenocarcinoma of the pancreas
Stomach cancer.

OMIM: FEZF1-AS1

rs3958046 of FEZF1-AS1 is a candidate gene for ADHD.¹⁹¹¹⁹²

rs11767283 correlates with age at first sexual intercourse
rs11767283 correlates with nutrition
rs145467198 correlates with heel bone mineral density
rs7779018 correlates with schizophrenia

1.192. LOC100507468

LOC100507468 has 150 functional associations with biological entities spanning 5 categories (organism, disease, phenotype or trait, chemical, cell line, cell type or tissue, gene, protein, or microRNA).¹⁹³

One study found LOC100507468 (variant rs1195234) to be one of 96 ADHD candidate genes.⁵²

1.194. LINC00355, Long Intergenic Non-Protein Coding RNA 355

Other names: NONHSAG013685.2; NONHSAG013688.2; NONHSAG013687.2; HSALNG0097622; HSALNG0097626; HSALNG0097627; LINC00355

LINC00355 is an RNA gene that belongs to the lncRNA class.¹⁹⁴
LINC00355 is associated with

Bladder Cancer

One study found LINC00355 (variant rs9528776) as one of 96 ADHD candidate genes.⁵²

1.197. LOC101927967, Uncharacterized LOC101927967

Other names: ONHSAG028283.2; SALNG0016229; HSALNG0016258; Lnc-LRRTM4-3

LOC101927967 is an RNA gene and belongs to the lncRNA class.¹⁹⁵

One study found LOC101927967 (variant rs1819004) as one of 96 candidate genes.⁵²

1.198. IFNG-AS1, IFNG antisense RNA 1

Other names: LincR-Ifng-3’AS; Tmevpg1; NEST; Theiler’S Murine Encephalomyelitis Virus Persistence Candidate Gene 1; FNG Antisense RNA 1; NONHSAG011599.2; HSALNG0092137; GS1-410F4.2; IFNG-AS1

IFNG-AS1 is an RNA gene and belongs to the lncRNA class.¹⁹⁶
IFNG-AS1 is associated with

Ulcerative colitis
Sjogren’s syndrome

One study found IFNG-AS1 (variant rs17629076) to be one of 96 ADHD candidate genes.⁵²

1.200. LOC101929484

We did not find any information on LOC101929484.

One study found LOC101929484 (variant rs2343365) to be one of 96 ADHD candidate genes.⁵²

1.201. LOC100133050, glucuronidase beta pseudogene

We have not found any information for LOC100133050.

One study found LOC100133050 (variant rs7717154) to be one of 96 ADHD candidate genes.⁵²

1.204. C6orf123, LINC01558, Long Intergenic Non-Protein Coding RNA 1558

Additional names: DJ431P23.4; C6orf123; HGC6.2; Long Intergenic Non-Protein Coding RNA 1557; LINC01557; Uncharacterized Protein Encoded By LINC01558; Chromosome 6 Open Reading Frame 123; NONHSAG045429.2; Protein HGC6.2; HSALNG0055207; LINC01558

C6orf123 (LINC01558) is an RNA gene that belongs to the lncRNA class.¹⁹⁷

One study found C6orf123 (variant rs543930) to be one of 96 ADHD candidate genes.⁵²

1.205. LINC01364, Long Intergenic Non-Protein Coding RNA 1364

Other names: NONHSAG001996.2; SALNG0004963; LINC01364

LINC01364 is an RNA gene that belongs to the lncRNA class.¹⁹⁸

One study found LINC01364 (variant rs12745339) as one of 96 ADHD candidate genes.⁵²

1.213. LOC101929184

We could not find any information for LOC101929184,

One study found LOC101929184 (variant rs12757080) to be one of 96 ADHD candidate genes.⁵²

1.215. LOC101927797

We could not find any information for LOC101927797.

One study found LOC101927797 (variant rs2824866) to be one of 96 ADHD candidate genes.⁵²

1.216. LINC02229:9, LOC101928769

Other names: NSG00000250313; RP11-5P22.3; ENSG00000250313.2; OTTHUMG00000162359.2; LINC02229¹⁹⁹

LINC02229 is an RNA gene and belongs to the lncRNA class.²⁰⁰

LOC101928769 appears to correlate with decreased hippocamus volume.²⁰¹

One study found LOC101928769 (variant rs6865656 and variant rs2968194) as one of 96 ADHD candidate genes.⁵²

1.217. MIR4255, MicroRNA 4255

Other names: Hsa-Mir-4255; MIMAT0016885; Hsa-MiR-4255; MI0015863

MIR4255 is an RNA gene belonging to the class of miRNA.²⁰²

MicroRNAs (miRNAs) are short (20-24 nt) noncoding RNAs involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs), which can be either protein-coding or noncoding. The primary transcript is cleaved by the enzyme Drosha ribonuclease III to generate an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which in turn is cleaved by the cytoplasmic ribonuclease Dicer to generate the mature miRNA and antisense miRNA star products (miRNA*). The mature miRNA is incorporated into an RNA-induced silencing complex (RISC) that recognizes target mRNAs by incomplete base pairing with the miRNA, leading in most cases to translational inhibition or destabilization of the target mRNA. RefSeq depicts the likely microRNA stem-loop. [provided by RefSeq, Sep 2009]

One study found MIR4255 (variant rs11264025) to be one of 96 ADHD candidate genes.⁵²

1.224. LINC01377, Long Intergenic Non-Protein Coding RNA 1377

Other names: NONHSAG039702.2; CTD-2029E14.1; HSALNG0039710; Lnc-IRX1-5

LINC01377 is an RNA gene that belongs to the lncRNA class.²⁰³

One study found LINC01377 (variant rs469546) as one of 96 ADHD candidate genes.⁵²

1.239. CASC17, Cancer Susceptibility 17

Other names: LINC00600; Cancer Susceptibility Candidate 17; Cancer Susceptibility 17; Long Intergenic Non-Protein Coding RNA 600; NONHSAG022649.2; HSALNG0118488; CASC17

CASC17 is an RNA gene and belongs to the class of lncRNAs.²⁰⁴
CASC17 is associated with Robinow syndrome, autosomal recessive 1.

One study found CASC17 (variant rs7224246) to be one of 96 ADHD candidate genes.⁵²

1.289. LINC02497, Long Intergenic Non-Protein Coding RNA 2497

Other names: NONHSAG037712.2; HSALNG0033638; LINC02497

LINC02497 is an RNA gene that belongs to the lncRNA class.²⁰⁵

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.290. LINC00461, Long Intergenic Non-Protein Coding RNA 461

Other names: EyeLinc1; ECONEXIN; NDIME; Neural Differentiation Initiation Of MEF2C Expression; LOC645323; Evolutionary Conserved And Expressed In Neural Tissues (ECONEXIN); Evolutionary Conserved And Expressed In Neural Tissues; Visual Cortex Expressed; Visual Cortex-Expressed; NONHSAG040968.2; NONHSAG040969.2; HSALNG0043367; HSALNG0043368; LincRNA 461; LINC00461; Visc-1a; Visc-1b; Visc-2; Visc; VISC

LINC00461 is an RNA gene and belongs to the lncRNA class (mir-9/mir-79 microRNA precursor family RF00237). LINC00461 is an evolutionarily conserved gene that produces alternatively spliced long noncoding RNAs that may be expressed primarily in the brain and visual cortex. These transcripts may be involved in tumorigenesis because depletion by siRNA suppresses glioma cell division. The transcripts may bind to miR-411-5p and Argonaut 2 and regulate their activity, altering the expression of genes involved in tumor growth.²⁰⁶
LINC00461 is associated with

Glioma
Cataract 24.

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.291. MIR9-2, MicroRNA 9-2

Other names: Hsa-MiR-9-3p; Hsa-MiR-9-5p; Hsa-Mir-9-2; MIRN9-2; Hsa-Mir-9-P2_pre; MIMAT0000441; MIMAT0000442; MI0000467; MiRNA9-2; Mir-9-2; RF00237

MIR9-2 is an RNA gene belonging to the class of miRNAs (mir-9/mir-79 microRNA precursor family RF00237). microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs), which can be either protein-coding or non-coding. The primary transcript is cleaved by the enzyme Drosha ribonuclease III to generate an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which in turn is cleaved by the cytoplasmic ribonuclease Dicer to generate the mature miRNA and antisense miRNA star products (miRNA*). The mature miRNA is incorporated into an RNA-induced silencing complex (RISC) that recognizes target mRNAs by incomplete base pairing with the miRNA, leading in most cases to translational inhibition or destabilization of the target mRNA. RefSeq represents the likely microRNA stem-loop.²⁰⁷
MIR9-2 is associated with

oral squamous cell carcinoma
Glioblastoma

Related signaling pathways:

Transition from epithelium to mesenchyme in colorectal cancer.

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.292. LINC02060, Long Intergenic Non-Protein Coding RNA 2060

Other names: NONHSAG040966.2; HSALNG0043365; CTC-498M16.2; LINC02060

LINC02060 is an RNA gene of the lncRNA class.²⁰⁸
This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.293. TMEM161B-AS1, TMEM161B Divergent Transcript

Other names: TMEM161B-DT, Linc-POLR3G-8; TMEM161B antisense RNA 1; TMEM161B antisense RNA 1; NONHSAG040958.2; SALNG0043357; HSALNG0043358; CTC-358I24.1; Lnc-RASA1-4

TMEM161B-DT is an RNA gene of the lncRNA class.²⁰⁹
This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.294. MIR3666, MicroRNA 3666

Other names: Hsa-Mir-3666; MIMAT0018088; Hsa-MiR-3666; MI0016067

MIR3666 is an RNA gene belonging to the class of miRNAs. microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs involved in the post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs), which can be either protein-coding or non-coding. The primary transcript is cleaved by the enzyme Drosha ribonuclease III to generate an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which in turn is cleaved by the cytoplasmic ribonuclease Dicer to generate the mature miRNA and antisense miRNA star products (miRNA*). The mature miRNA is incorporated into an RNA-induced silencing complex (RISC) that recognizes target mRNAs by incomplete base pairing with the miRNA, leading in most cases to translational inhibition or destabilization of the target mRNA. RefSeq represents the likely microRNA stem-loop.²¹⁰

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.295. LINC01288, Long Intergenic Non-Protein Coding RNA 1288

Other names: TCONS_00014671; NONHSAG049959.2; HSALNG0064496; LINC01288

LINC01288 is an RNA gene of the lncRNA class.²¹¹

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.300. LINC01572, Long Intergenic Non-Protein Coding RNA 1572

Other names: NONHSAG019920.2; NONHSAG019917.2; HSALNG0112544; LINC01572

LINC01572 is an RNA gene of the lncRNA class.²¹²

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁹

1.301. Intergenic, Locus 2, Chromosome 1, Base position 96602440, Variant rs1222063

This “gene” was identified as an ADHD candidate gene in a large GWAS.¹⁹

However, in one study, the frequency distribution of genotype rs1222063 did not meet the Hardy-Weinberg equilibrium test (P < 0.05) and was therefore not representative of the population.²¹³

1.302. Intergenic locus 4, chromosome 3, base position 20669071, variant rs4858241

This “gene” was identified as an ADHD candidate gene in a large GWAS.¹⁹

One study found increased Stroop response times.²¹³

1.313. LncRNA HULC

Increased expression of CLOCK, PER1, lncRNA HULC, and lncRNA UCA1 correlated with evening chronotype, problems falling asleep and staying asleep, sleep-wake transition disorders, and excessive sleepiness in ADHD. There was no significant association between individual genes and specific sleep parameters.²¹⁴

1.314. LncRNA UCA1

Increased expression of CLOCK, PER1, lncRNA HULC, and lncRNA UCA1 correlated with evening chronotype, problems falling asleep and staying asleep, sleep-wake transition disorders, and excessive sleepiness in ADHD. There was no significant correlation between individual genes and specific sleep parameters.²¹⁴

1.317. DDX3X

DDX3X syndrome is genetic neurodevelopmental disorder that correlates with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities.²¹⁵

1.318. ATP9A

Genetically determined ATP9A deficiency causes ADHD and abnormal endosomal recycling by modulating the activity of RAB5 and RAB11.²¹⁶

There are several hundred other candidate genes that are not mentioned here.

Sitemap

2. Gene candidates without plausible pathway in relation to ADHD.

Genes with mechanisms whose mode of action in relation to ADHD is not comprehensible to us¶

2.24. CFTR, ciliary neurotrophic factor receptor gene, CNFTR (chromosome 9p13.3)¶

2.48. FADS2, FATTY ACID DESATURASE 2 (chromosome 11q12.2)¶

2.52. MTA3, METASTASIS-ASSOCIATED GENE 3 (chromosome 2)¶

2.68. FHIT, FRAGILE HISTIDINE TRIAD GENE (chromosome 3p14.2)¶

2.80. TMEM161B; TRANSMEMBRANE PROTEIN 161B¶

2.83. SNORC, Secondary Ossification Center Associated Regulator Of Chondrocyte Maturation¶

2.88. B4GALT2, UDP-GAL:BETA-GlcNAc BETA-1,4-GALACTOSYLTRANSFERASE, POLYPEPTIDE 2¶

2.92. TRIO, Trio Rho Guanine Nucleotide Exchange Factor¶

2.94. SYNE1, SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1¶

2.96. BMPR1B; Bone morphogenetic protein receptor type-1B¶

2.285. HAS3, Hyaluronan Synthase 3¶

2.103. ITIH3, Inter-Alpha-Trypsin Inhibitor Heavy Chain 3¶

2.113. ATP2C2, ATPase Secretory Pathway Ca2+ Transporting 2¶

2.118. MPP6, MAGUK p55 subfamily member 6¶

2.123. PALB2, Partner and localizer of BRCA2¶

2.124. ZNF385D, Zinc Finger Protein 385D¶

2.126. CHMP7, Charged Multivesicular Body Protein 7¶

2.128. MUCL3, DPCR1, Human diffuse panbronchiolitis critical region 1, Real Time PCR Primer Set¶

2.129. PIWIL4, Piwi Like RNA-Mediated Gene Silencing 4¶

2.130. AK8, adenylate kinase 8¶

2.131. CFAP221, Cilia And Flagella Associated Protein 221¶

Genes whose pathway of action in relation to ADHD we have not yet reviewed¶

1.132. CEP112, Centrosomal Protein 112¶

1.133. KIF6, Kinesin Family Member 6¶

1.135. NCKAP5, NCK Associated Protein 5¶

1.136. SPATA33, Spermatogenesis Associated 33¶

1.137. CDK10, Cyclin Dependent Kinase 10¶

1.138. PPP1R11, PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 11¶

1.140. NME5, NME/NM23 FAMILY, MEMBER 5¶

1.141. ABHD5, ABHYDROLASE DOMAIN-CONTAINING 5¶

1.142. GMPR2, GUANOSINE MONOPHOSPHATE REDUCTASE 2¶

1.144. BLOC1S2, BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 2¶

1.145. KIAA0319L, KIAA0319-LIKE¶

1.146. FMNL3, Formin Like 3¶

1.147. CCDC138, Coiled-Coil Domain Containing 138¶

1.148. TMBIM6, Transmembrane BAX Inhibitor Motif Containing 6¶

1.149. SV2A, Synaptic Vesicle Glycoprotein 2A¶

1.150. TARBP1, TAR (HIV-1) RNA Binding Protein 1¶

1.151. TATDN3¶

1.152. ALS2CR8, CARF¶

1.153. ST3GAL3¶

1.154. ELAVL4¶

1.155. NBEAL1¶

1.156. FGFR3¶

1.157. ACAD11, Acyl-CoA Dehydrogenase Family Member 11¶

1.158. CNPY2¶

1.159. PACC1, TMEM206¶

1.160. BST1, Bone Marrow Stromal Cell Antigen 1¶

1.161. RASSF4, Ras Association Domain Family Member 4¶

1.163. RAPGEF5, Rap Guanine Nucleotide Exchange Factor 5¶

1.164. MVP, Major Vault Protein¶

1.165. RPS20, Ribosomal Protein S20¶

1.166. RASGRP4, RAS Guanyl Releasing Protein 4¶

1.167. MAP1A, Microtubule-associated protein 1A¶

1.168. FBXO25, F-BOX ONLY PROTEIN 25¶

1.169. TRAPPC9, TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 9¶

1.170. MEF2C, MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C¶

1.171. TNRC6B, TRINUCLEOTIDE REPEAT-CONTAINING GENE 6B¶

1.172. 22Q11.2¶

1.173. EPHA5, EPH receptor A5¶

1.174. RIMS1, Regulating Synaptic Membrane Exocytosis 1¶

1.175. NRG3, Neuregulin 3¶

1.176. TENM4, Teneurin Transmembrane Protein 4¶

1.178. MDGA2, MAM Domain Containing Glycosylphosphatidylinositol Anchor 2¶

1.179. RBFOX1, RNA Binding Fox-1 Homolog 1¶

1.180. LIG4, DNA Ligase 4¶

1.181. NEDD4L, NEDD4 Like E3 Ubiquitin Protein Ligase¶

1.182. BMP2, Bone Morphogenetic Protein 2¶

1.182. FAM19A4, TAFA4, TAFA Chemokine Like Family Member 4¶

1.183. ATXN8OS, ATXN8 Opposite Strand LncRNA¶

1.184. PPP1R26-AS1¶

1.185. BCR, BCR Activator Of RhoGEF And GTPase¶

1.186. ZBTB7C, Zinc Finger And BTB Domain Containing 7C¶

1.187. TSPAN11, Tetraspanin 11¶

1.188. GRIP1, Glutamate Receptor Interacting Protein 1¶

1.189. PRDM2, PR/SET Domain 2¶

1.190. LINC00609, Long Intergenic Non-Protein Coding RNA 609¶

Genes with mechanisms whose mode of action in relation to ADHD is not comprehensible to us

2.24. CFTR, ciliary neurotrophic factor receptor gene, CNFTR (chromosome 9p13.3)

2.48. FADS2, FATTY ACID DESATURASE 2 (chromosome 11q12.2)

2.52. MTA3, METASTASIS-ASSOCIATED GENE 3 (chromosome 2)

2.68. FHIT, FRAGILE HISTIDINE TRIAD GENE (chromosome 3p14.2)

2.80. TMEM161B; TRANSMEMBRANE PROTEIN 161B

2.83. SNORC, Secondary Ossification Center Associated Regulator Of Chondrocyte Maturation

2.88. B4GALT2, UDP-GAL:BETA-GlcNAc BETA-1,4-GALACTOSYLTRANSFERASE, POLYPEPTIDE 2

2.92. TRIO, Trio Rho Guanine Nucleotide Exchange Factor

2.94. SYNE1, SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1

2.96. BMPR1B; Bone morphogenetic protein receptor type-1B

2.285. HAS3, Hyaluronan Synthase 3

2.103. ITIH3, Inter-Alpha-Trypsin Inhibitor Heavy Chain 3

2.113. ATP2C2, ATPase Secretory Pathway Ca2+ Transporting 2

2.118. MPP6, MAGUK p55 subfamily member 6

2.123. PALB2, Partner and localizer of BRCA2

2.124. ZNF385D, Zinc Finger Protein 385D

2.126. CHMP7, Charged Multivesicular Body Protein 7

2.128. MUCL3, DPCR1, Human diffuse panbronchiolitis critical region 1, Real Time PCR Primer Set

2.129. PIWIL4, Piwi Like RNA-Mediated Gene Silencing 4

2.130. AK8, adenylate kinase 8

2.131. CFAP221, Cilia And Flagella Associated Protein 221

Genes whose pathway of action in relation to ADHD we have not yet reviewed

1.132. CEP112, Centrosomal Protein 112

1.133. KIF6, Kinesin Family Member 6

1.135. NCKAP5, NCK Associated Protein 5

1.136. SPATA33, Spermatogenesis Associated 33

1.137. CDK10, Cyclin Dependent Kinase 10

1.138. PPP1R11, PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 11

1.140. NME5, NME/NM23 FAMILY, MEMBER 5

1.141. ABHD5, ABHYDROLASE DOMAIN-CONTAINING 5

1.142. GMPR2, GUANOSINE MONOPHOSPHATE REDUCTASE 2

1.144. BLOC1S2, BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 2

1.145. KIAA0319L, KIAA0319-LIKE

1.146. FMNL3, Formin Like 3

1.147. CCDC138, Coiled-Coil Domain Containing 138

1.148. TMBIM6, Transmembrane BAX Inhibitor Motif Containing 6

1.149. SV2A, Synaptic Vesicle Glycoprotein 2A

1.150. TARBP1, TAR (HIV-1) RNA Binding Protein 1

1.151. TATDN3

1.152. ALS2CR8, CARF

1.153. ST3GAL3

1.154. ELAVL4

1.155. NBEAL1

1.156. FGFR3

1.157. ACAD11, Acyl-CoA Dehydrogenase Family Member 11

1.158. CNPY2

1.159. PACC1, TMEM206

1.160. BST1, Bone Marrow Stromal Cell Antigen 1

1.161. RASSF4, Ras Association Domain Family Member 4

1.163. RAPGEF5, Rap Guanine Nucleotide Exchange Factor 5

1.164. MVP, Major Vault Protein

1.165. RPS20, Ribosomal Protein S20

1.166. RASGRP4, RAS Guanyl Releasing Protein 4

1.167. MAP1A, Microtubule-associated protein 1A

1.168. FBXO25, F-BOX ONLY PROTEIN 25

1.169. TRAPPC9, TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 9

1.170. MEF2C, MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C

1.171. TNRC6B, TRINUCLEOTIDE REPEAT-CONTAINING GENE 6B

1.172. 22Q11.2

1.173. EPHA5, EPH receptor A5

1.174. RIMS1, Regulating Synaptic Membrane Exocytosis 1

1.175. NRG3, Neuregulin 3

1.176. TENM4, Teneurin Transmembrane Protein 4

1.178. MDGA2, MAM Domain Containing Glycosylphosphatidylinositol Anchor 2

1.179. RBFOX1, RNA Binding Fox-1 Homolog 1

1.180. LIG4, DNA Ligase 4

1.181. NEDD4L, NEDD4 Like E3 Ubiquitin Protein Ligase

1.182. BMP2, Bone Morphogenetic Protein 2

1.182. FAM19A4, TAFA4, TAFA Chemokine Like Family Member 4

1.183. ATXN8OS, ATXN8 Opposite Strand LncRNA

1.184. PPP1R26-AS1

1.185. BCR, BCR Activator Of RhoGEF And GTPase

1.186. ZBTB7C, Zinc Finger And BTB Domain Containing 7C

1.187. TSPAN11, Tetraspanin 11

1.188. GRIP1, Glutamate Receptor Interacting Protein 1

1.189. PRDM2, PR/SET Domain 2

1.190. LINC00609, Long Intergenic Non-Protein Coding RNA 609

1.191. NAV1, Neuron Navigator 1

1.195. GIMAP6, GTPase, IMAP Family Member 6