GJA1 – Erythrokeratodermia Variabilis

Erythrokeratodermia variabilis et progressiva (EKVP) is a rare autosomal dominant genodermatosis characterized by transient, fast-moving erythema and persistent brown hyperkeratotic plaques. Two unrelated Chinese patients—a 12-year-old boy and a 7-year-old girl—presented with symmetrical erythematous patches and hyperkeratotic plaques. Sanger sequencing identified two de novo heterozygous missense variants in GJA1: c.848C>T (p.Pro283Leu) and c.869C>A (p.Thr290Asn), absent in 100 controls and unaffected relatives ([PMID:30924322]).

Functional assessment in rat epidermal keratinocytes expressing P283L and/or T290N variants demonstrated prototypical gap junction formation but no evidence of augmented hemichannel activity. Live-cell trafficking assays revealed that each variant individually, or in combination, significantly extended Cx43 residence at the cell surface and delayed its degradation, consistent with altered turnover kinetics as a mechanism of pathogenesis ([PMID:35008913]). A recent review consolidates evidence that AD GJA1 variants in EKVP impair gap junction function through diverse molecular defects including mislocalization and dysregulated channel turnover ([PMID:39513663]).

References

• Molecular genetics & genomic medicine • 2019 • Two de novo GJA1 mutation in two sporadic patients with erythrokeratodermia variabilis et progressiva. PMID:30924322
• International journal of molecular sciences • 2022 • Interrogation of Carboxy-Terminus Localized GJA1 Variants Associated with Erythrokeratodermia Variabilis et Progressiva. PMID:35008913
• The Biochemical journal • 2024 • The genetic and molecular basis of a connexin-linked skin disease. PMID:39513663

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