Background: Erythrokeratodermia variabilis (EKV) is an autosomal dominant or recessive genodermatosis characterized by the coexistence of randomly occurring, transient, erythematous patches and hyperkeratosis of the skin. The disorder has been mapped to chromosome 1p35.1 but is genetically heterogeneous. EKV may be caused by pathogenic mutations in one of two neighbouring connexin genes, GJB3 and GJB4, encoding the gap junction proteins Cx31 and Cx30.3, respectively. Twelve distinct mutations identified to date cluster either at the cytoplasmic amino-terminus or in the four transmembrane domains.
Objectives: To report a large family with EKV and an unrelated sporadic case.
Methods: DNA amplification and mutation analysis, followed by denaturing high-performance liquid chromatography to confirm the segregation of the mutations in the two families with EKV.
Results: A novel, recurrent GJB3 mutation (625C-->T; L209F) was identified in the family with EKV and in the unrelated sporadic case.
Conclusions: This mutation is the first to affect a conserved residue in the cytoplasmic carboxy-terminus of any connexin gene with a cutaneous phenotype, emphasizing its structural and/or functional importance.