Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and
erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized
erythrokeratodermia variabilis, and one with erythrokeratodermia and
ataxia. Another family had
Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both
erythrokeratodermia variabilis and
erythrokeratodermia with ataxia map to a common region in 1p34-p35. Multipoint linkage and haplotype analyses place
erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French-Canadian origin. In contrast, results excluded Greither's disease from the established
erythrokeratodermia variabilis gene region indicating genetic heterogeneity of erythrokeratodermias. Based on recombinations, two genes assigned to 1p34-p35 were excluded:
cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 (GJA4), a member of the
connexin gene family, maps within the
erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed
connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of
erythrokeratodermia variabilis.