Erythrokeratoderma variabilis caused by a recessive mutation in GJB3

Summary Background. Erythrokeratoderma variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the genes GJB3 and GJB4, which code for connexin (Cx)31 and Cx30.3, respectively, and contribute to the formation of functional gap junctions in the epidermis. Aim. To identify the molecular basis of recessive EKV in a consanguineous family of Middle Eastern origin. Methods. Direct sequencing and site-directed mutagenesis was used to search for the disease-causing mutation and identify its molecular consequences. Results. A novel missense mutation (c.G88A) was found in the human GJB3 gene, resulting in substitution of the amino acid isoleucine for valine at position 30 (p.V30I). Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation. Conclusions. Autosomal recessive inheritance should be considered when providing genetic counselling to consanguineous families at risk for EKV.