GJB4 – Erythrokeratodermia Variabilis

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by persistent hyperkeratotic plaques and transient erythematous patches. Pathogenic variants in the gap junction gene GJB4, encoding connexin 30.3, have been implicated in autosomal dominant forms of EKV (MONDO:0017851).

Autosomal dominant inheritance is supported by six unrelated probands (five families) harboring missense GJB4 variants, along with a sporadic late-onset case carrying c.109G>A (p.Val37Met) (PMID:12648223; PMID:34717022).

Segregation analysis in an extended Dutch family with c.35G>A (p.Gly12Asp) and in two families with c.411C>A (p.Phe137Leu) accounts for seven additional affected relatives segregating these alleles (PMID:12648223).

The variant spectrum includes at least six distinct missense changes: c.35G>A (p.Gly12Asp), c.65G>A (p.Arg22His), c.253A>C (p.Thr85Pro), c.411C>A (p.Phe137Leu), c.566T>A (p.Phe189Tyr), and c.109G>A (p.Val37Met), with no reported truncating alleles (PMID:12648223; PMID:34717022).

Functional studies demonstrate that EKV-linked GJB4 mutants impair gap junction assembly via a dominant-negative mechanism. Mutant connexin 30.3 is retained in the endoplasmic reticulum, reduces intercellular coupling, and can be partially rescued by co-expression of wild-type connexins (PMID:14583444; PMID:36861039).

Together, genetic segregation, multiple independent probands, and concordant functional data fulfill ClinGen criteria for a Strong gene–disease association. Routine screening of GJB4 for dominant missense variants is clinically useful for the diagnosis and genetic counseling of EKV. Key Take-home: GJB4 missense variant testing enhances diagnostic accuracy in erythrokeratodermia variabilis.

References

• Experimental dermatology • 2022 • Erythrokeratodermia variabilis et progressiva due to a novel mutation in GJB4. PMID:34717022
• The Journal of investigative dermatology • 2003 • Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. PMID:12648223
• Human molecular genetics • 2003 • Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. PMID:14583444
• Frontiers in cell and developmental biology • 2023 • GJB4 variants linked to skin disease exhibit a trafficking deficiency en route to gap junction formation that can be restored by co-expression of select connexins. PMID:36861039
• The British journal of dermatology • 2005 • Clinical and genetic heterogeneity of erythrokeratoderma variabilis. PMID:16297190

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