GJB2 – Autosomal Dominant Nonsyndromic Hearing Loss

Autosomal dominant nonsyndromic hearing loss (DFNA3) is caused by heterozygous mutations in GJB2 (connexin 26), which encodes a gap junction protein critical for potassium recycling in the cochlea. While recessive GJB2 mutations underlie DFNB1 hearing loss, a subset of missense variants exert dominant-negative effects leading to progressive sensorineural impairment.

Genetic Evidence

The c.136G>A (p.Asp46Asn) variant segregates with postlingual hearing loss in two unrelated Iranian families (founder effect), with complete cosegregation in 12 affected relatives across both pedigrees (PMID:21484990). Additional dominant missense alleles—c.260C>T (p.Pro87Leu) and c.427C>T (p.Arg143Trp)—have been observed in isolated families with non-syndromic deafness, demonstrating autosomal dominant inheritance and intra-family segregation (PMID:9393973, PMID:9856479). Variants cluster in extracellular loops and transmembrane domains, with no loss-of-function truncating alleles reported for DFNA3.

Functional Evidence

In vitro paired oocyte and HeLa cell assays show that P87L and R143W mutants fail to form functional gap junctions and dominantly inhibit wild-type Cx26 channel activity without affecting GJIC localization (PMID:9393973). The W44C allele similarly exhibits dominant-negative suppression of dye transfer and altered gating (PMID:12064630). Site-directed mutagenesis at residues Gly59 and Asp66 reveals selective trans-dominant effects on co-expressed connexins (PMID:12668604).

Animal Model

A transgenic mouse expressing the R75W mutant under the native promoter exhibits profound hearing loss, degeneration of the organ of Corti, and supporting cell defects, recapitulating DFNA3 pathology and confirming a dominant-negative mechanism in vivo (PMID:12700168).

Conflicting Evidence

The M34T variant (c.101T>C) has been extensively screened and shown not to segregate with autosomal dominant hearing loss, indicating a benign or hypomorphic role in isolation (PMID:11216656).

Integrating genetic segregation, dominant-negative functional assays, and an in vivo model, the evidence meets ClinGen criteria for a Definitive association between GJB2 and autosomal dominant nonsyndromic hearing loss. Screening for GJB2 dominant alleles informs diagnosis and genetic counseling in familial hearing impairment.

References

• American Journal of Medical Genetics Part A • 2011 • Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss. PMID:21484990
• Oncogene • 1997 • Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes. PMID:9393973
• Human Genetics • 1998 • Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. PMID:9856479
• Human Molecular Genetics • 2003 • Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. PMID:12700168
• Genetic Testing • 2000 • The M34T allele variant of connexin 26. PMID:11216656

Evidence Based Scoring (AI generated)