Linkage Studies in Erythrokeratodermias: Fine Mapping, Genetic Heterogeneity, and Analysis of Candidate Genes

Abstract

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.

Connexins: a connection with the skin

“…However, individual plaques may also change in size and shape, or regress leaving normal skin. In about half of all EKV families, hyperkeratosis involves palms and soles as a patchy or diffuse palmoplantar keratoderma, often associated with peeling (96)(97)(98). Both the hyperkeratosis and erythema may be triggered by internal and/or external factors, including stress, sudden temperature changes, mechanical friction, and sun exposure.…”

“…Moreover, it is known to be expressed in rodent epidermis and endothelial cells. Although direct sequencing of the coding region in a panel of 12 unrelated EKV patients revealed several sequence variations, including a novel polymorphism within the putative CT domain of Cx37 (P319S), no pathogenic mutations were detected, therefore excluding GJA4 as disease gene (96). It might be of interest to note that re- cently this polymorphism was identified as a possible prognostic marker for the development of athero-sclerotic plaques (108).…”

Mutation in the Gene for Connexin 30.3 in a Family with Erythrokeratodermia Variabilis

“…Generally, EKV presents at birth or begins during early life. All families with EKV so far have shown mapping to chromosome 1p34-35, between the markers D1S496 and D1S186, with a maximum LOD score (Z max ) of 12.88 for D1S472 (Richard et al 1997). These markers define a 2.6-cM candidate interval that contains a cluster of three genes for Cx: GJB3, encoding Cx31, GJA4, encoding Cx37, and GJB5, encoding Cx31.1 (van der Schroeff et al 1988;Richard et al 1997).…”

“…All families with EKV so far have shown mapping to chromosome 1p34-35, between the markers D1S496 and D1S186, with a maximum LOD score (Z max ) of 12.88 for D1S472 (Richard et al 1997). These markers define a 2.6-cM candidate interval that contains a cluster of three genes for Cx: GJB3, encoding Cx31, GJA4, encoding Cx37, and GJB5, encoding Cx31.1 (van der Schroeff et al 1988;Richard et al 1997). Subsequently, six distinct Cx31 mutations were found-but only in 8 of 20 EKV families investigated, suggesting that EKV is genetically heterogeneous (Richard et al 1998(Richard et al , 2000Wilgoss et al 1999).…”

“…To see whether EKV in this family also shows linkage to 1p34-p35, as described elsewhere (Richard et al 1997), linkage analysis with the three Généthon microsatellite markers D1S186, D1S496, and D1S472 was performed (Dib et al 1996). The Z max (2.343, at recombination fraction 0) of the two-point analyses, when…”