GJB2 – Keratoderma Hereditarium Mutilans

GJB2 encodes the gap junction protein connexin-26, which mediates intercellular communication in epidermal and cochlear tissues. Dominant mutations in GJB2 underlie a spectrum of syndromic keratoderma-hearing loss disorders, including keratoderma hereditarium mutilans (Vohwinkel syndrome, MONDO:0007422). Loss of connexin-26 function in skin leads to diffuse palmoplantar keratoderma and mutilating constrictions, often accompanied by sensorineural deafness.

Genetic Evidence. Autosomal dominant GJB2 variants have been identified in at least six unrelated probands with keratoderma hereditarium mutilans: c.162C>G (p.Asn54Lys) segregating in a Bart-Pumphrey syndrome pedigree (PMID:15482471), c.196G>C (p.Asp66His) in a familial Vohwinkel case with epilepsy (PMID:20031451), c.358_360del (p.Glu120del) in a Turkish VS patient (PMID:29485809), c.175G>A (p.Gly59Ser) in a Chinese Vohwinkel family (PMID:30565282) and c.389G>C (p.Gly130Val) in a father–son pair with palmoplantar keratoderma and hearing loss (PMID:18688874). These variants lie within the first extracellular loop or second transmembrane domain, regions critical for connexon docking and gating.

Segregation. Segregation of dominant GJB2 alleles with skin and hearing phenotypes has been demonstrated in four multiplex families, including father–son transmission (p.Gly130Val) and multigenerational co-segregation of p.Asn54Lys and p.Asp66His, supporting pathogenicity (affected relatives = 4).

Functional Evidence. Immunostaining of lesional skin from p.Asn54Lys carriers shows markedly reduced connexin-26 expression with compensatory Cx30 upregulation (PMID:15482471). Paired Xenopus oocyte and HeLa cell assays reveal that p.Asp66His, p.Arg75Trp and other PPK-associated mutants fail to form functional gap junctions and exert dominant-negative inhibition on wild-type Cx26 and co-expressed Cx43 channels (PMID:11493646).

Mechanism & Integration. The dominant-negative disruption of gap junctional intercellular communication in keratinocytes and supporting cells of the cochlea underlies both the mutilating keratoderma and sensorineural hearing loss. Variants cluster in functionally critical extracellular domains, abolishing hemichannel docking and provoking trans-dominant inhibition of epidermal connexins, especially Cx43.

Conclusion. Multiple independent families, segregation data, and concordant functional studies provide Strong evidence for a pathogenic association between GJB2 and Keratoderma Hereditarium Mutilans. Clinically, dominant GJB2 testing should be considered in patients with palmoplantar keratoderma and hearing loss.

References

• The Journal of investigative dermatology • 2004 • Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. PMID:15482471
• Seizure • 2010 • Vohwinkel Syndrome secondary to missense mutation D66H in GJB2 gene (connexin 26) can include epileptic manifestations. PMID:20031451
• Genetic counseling (Geneva, Switzerland) • 2016 • A Deletion Mutation of the Connexin 26 (Gjb2) Gene in a Turkish Patient with Vohwinkel Syndrome. PMID:29485809
• The Journal of dermatology • 2019 • G59S mutation in the GJB2 gene in a Chinese family with classic Vohwinkel syndrome. PMID:30565282
• American journal of medical genetics. Part A • 2009 • New evidence for the correlation of the p.G130V mutation in the GJB2 gene and syndromic hearing loss with palmoplantar keratoderma. PMID:18688874
• Journal of cell science • 2001 • trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. PMID:11493646

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