GJA1

Gene Facts

• HGNC Symbol: GJA1 (HGNC:4274)
• HGNC Name: gap junction protein alpha 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: ODDD, GJAL
• Alias symbols: CX43, ODD, ODOD, SDTY3
• %HI: 1.17
• pLI: 0.96
• LOEUF: 0.52
• Cytoband: 6q22.31
• Genomic Coordinates:

  GRCh37/hg19:	chr6:121756792-121770873
  GRCh38/hg38:	chr6:121435646-121449727

• MANE Select Transcript: NM_000165.5 ENST00000282561.4
• Function: Gap junction protein that acts as a regulator of bladder capacity. A gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, th... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-20609
• ClinGen Curation ID: CCID:007208
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/20/2013

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency
• HI Evidence Comments: Mutations in the GJA1 gene (OMIM: 121014) have been identified in several clinically and genetically heterogeneous groups of autosomal dominant and recessive diseases: Syndactyly, type III (OMIM: 186100), Oculodentodigital dysplasia, autosomal recessive (OMIM: 257850), Oculodentodigital dysplasia, autosomal dominant (ODDD-AD, OMIM: 164200), Hypoplastic left heart syndrome 1 (OMIM: 241550), Hallermann-Streiff syndrome (OMIM: 234100) and Atrioventricular septal defect 3 (OMIM: 600309). The GJA1gene product, connexin 43, is a transmembrane protein that assembles in groups of six (hemichannels) involved in the formation of gap junctions. In 2003, Paznekas et al, (PMID: 12457340), identified 16 missense mutations and one codon duplication in 12 familial and 5 sporadic cases of ODDD. To date, more than 65 known mutations within the coding sequence of the GJA1 gene have been identified (summarized in Paznekas et al, PMID: 19338053 and Huang et al. PMID: 23606748). The majority of mutations (85%) have been missense mutations with the remaining mutations being codon duplications and deletions as well as frameshift mutations. The identified frameshift mutations occur in the latter portion of the coding regions and are believed to also generate truncated dominant negative or a gain of function connexin 43 protein products (Gong et al, 2006. PMID: 16891658). In addition, an autosomal recessive homozygous truncating mutation (p.R33X) was identified as being inherited from heterozygous unaffected parents (Richardson et al, PubMed: 16816024). The observation that the majority of identified mutations are missense mutations, together with the rarity of deletions or truncating mutations, suggests that either a dominant negative or a gain of function mechanism. There is no evidence to suggest that loss of a single copy of GJA1 causes an abnormal phenotype. Variation in GJA1 was reported in individuals with nonsyndromic hearing loss; however, the overall evidence that GJA1, when altered, causes nonsyndromic hearing loss was expert reviewed by the ClinGen Hearing Loss Working Group and classified as DISPUTED.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There is no evidence to suggest that gain of a single copy of GJA1 causes an abnormal phenotype.