Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis

Erythrokeratodermia variabilis (EKV) is an autosomal dominant keratinizatio n disorder characterized by migratory erythematous lesions and fixed kerato tic plaques. All families with EKV show mapping to chromosome 1p34-p35, and mutations in the gene for connexin 31 (Cx31) have been reported in some bu t not all families. We studied eight affected and three healthy subjects in an Israeli family, of Kurdish origin, with EKV. After having mapped the di sorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37. Further investigation revealed a heterozygous T-->C tran sition leading to the missense mutation (F137L) in the human gene for Cx30. 3 that colocalizes on chromosome 1p34-p35. This nucleotide change cosegrega ted with the disease and was not found in 200 alleles from normal individua ls. This mutation concerns a highly conserved phenylalanine, in the third t ransmembrane region of the Cx30.3 molecule, known to be implicated in the w all formation of the gap-junction pore. Our results show that mutations in the gene for Cx30.3 can be causally involved in EKV and point to genetic he terogeneity of this disorder. Furthermore, we suggest that our family prese nts a new type of EKV because of the hitherto unreported association with e rythema gyratum repens.