GJB3 – Erythrokeratodermia variabilis

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by transient, figurate erythematous patches and fixed hyperkeratotic plaques affecting the epidermis. The disorder is most commonly inherited in an autosomal dominant pattern and has been linked to pathogenic variants in the gap junction gene GJB3, which encodes connexin 31 (Cx31), in addition to connexin 30.3 and connexin 43 genes (erythrokeratodermia variabilis).

Genetic evidence for GJB3-associated EKV includes identification of missense mutations in multiple unrelated families and sporadic cases. A cohort study of two families and three sporadic patients reported three novel heterozygous variants, including c.411C>G (p.Phe137Leu), co-segregating with disease in 6 out of 17 families investigated (PMID:10798362). A recurrent L209F variant was detected in a large pedigree and an unrelated case, underscoring its pathogenicity (PMID:15948974). Rare autosomal recessive transmission has also been documented with a homozygous c.88G>A (p.Val30Ile) mutation in a consanguineous Middle Eastern family (PMID:21564177).

Segregation analysis across these studies demonstrates autosomal dominant inheritance with multiple affected individuals per family, including three affected relatives in one pedigree (PMID:10798362). Case reports consistently describe migratory erythematous and hyperkeratotic skin lesions.

Functional assays reveal that EKV-linked Cx31 mutants (e.g., p.Arg42Pro, p.Gly12Asp, p.Asp66del) display defective trafficking to the plasma membrane, impaired gap junction intercellular communication, and a high incidence of keratinocyte cell death in vitro (PMID:12165562). The p.Gly12Asp variant disrupts channel function without affecting membrane targeting, indicating diverse mechanisms of pathogenicity (PMID:12702148).

A knock-in mouse model carrying the human p.Phe137Leu mutation exhibits reduced neurobiotin transfer and a dominant-negative impact on Cx43, recapitulating aspects of the human skin phenotype and confirming in vivo relevance (PMID:17446259). Moreover, EKV-associated Cx31 mutants induce endoplasmic reticulum stress and unfolded protein response markers, implicating aberrant protein folding in pathogenesis (PMID:19755382).

Integration of genetic and functional data supports a mechanism whereby dominant-negative and cytotoxic effects of Cx31 variants impair gap junction assembly and keratinocyte homeostasis. The broad spectrum of missense alleles, reproducible segregation across pedigrees, and concordant experimental findings meet criteria for a Definitive gene–disease association. Comprehensive genetic testing for GJB3 variants is clinically actionable for diagnosis and family counseling. Key Take-home: GJB3 mutations cause autosomal dominant EKV through dominant-negative gap junction dysfunction and ER stress, guiding targeted molecular diagnosis and potential therapeutic interventions.

References

• Human genetics • 2000 • The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3. PMID:10798362
• Clinical and experimental dermatology • 2011 • Erythrokeratoderma variabilis caused by a recessive mutation in GJB3. PMID:21564177
• Human molecular genetics • 2002 • Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. PMID:12165562
• The British journal of dermatology • 2005 • A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis. PMID:15948974
• Human molecular genetics • 2009 • EKV mutant connexin 31 associated cell death is mediated by ER stress. PMID:19755382

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