Erythrokeratodermia variabilis (EKV) is an autosomal dominant keratinization disorder characterized by migratory erythematous lesions and fixed keratotic 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 but not all families. We studied eight affected and three healthy subjects in an Israeli family, of Kurdish origin, with EKV. After having mapped the disorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37. Further investigation revealed a heterozygous TrC transition leading to the missense mutation (F137L) in the human gene for Cx30.3 that colocalizes on chromosome 1p34-p35. This nucleotide change cosegregated with the disease and was not found in 200 alleles from normal individuals. This mutation concerns a highly conserved phenylalanine, in the third transmembrane region of the Cx30.3 molecule, known to be implicated in the wall 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 heterogeneity of this disorder. Furthermore, we suggest that our family presents a new type of EKV because of the hitherto unreported association with erythema gyratum repens.Connexins (denoted by the prefix "Cx") are a family of polypeptides that form the subunits of the gap-junction channels. Members of the connexin family are characterized by four hydrophobic transmembrane domains (M1-M4) that are linked by one cytoplasmic and two extracellular (E1 and E2) loops. The N and C termini are located on the cytoplasmic membrane face. Extracellular-loop and transmembrane domains display the highest homology between the connexin family members, whereas the cytoplasmic loop and the C-terminal region are highly variable. Six connexin polypeptides assemble into a connexon, a hemichannel that interacts with its counterpart on adjacent cells to form a complete intercellular channel, thereby connecting the cytoplasm of neighboring cells (Yeager and Nicholson 1996). Gap junctions are composed of numerous aggregated con-

Erythrokeratodermia variabilis (EKV) is a skin disorder characterized by variable (transient) erythemas and fixed keratosis. The disorder maps to chromosome 1p34-35, a location that contains the GJB3 gene encoding the gap junction protein connexin 31. Until now, only heterozygote mutations in the form of dominant inheritance have been described in this gene associated with EKV. We report here a homozygote mutation in the connexin 31 gene, found in a family that shows recessive inheritance of the disorder, thus providing the first molecular support for a recessive variant of EKV. The entire GJB3 coding sequence was scanned for mutations by sequencing. We detected a T-->C transition at position 101 of the coding sequence, which replaces a leucine with a proline at residue 34 of the protein (L34P). Evolutionary analysis shows that this mutation is located at a highly conserved region of connexin in the first putative transmembrane helix (TMH). In transfected keratinocytes, L34P connexin 31 had a cytoplasmic distribution, suggesting that the mutant form of this protein will not form normal gap junctions between adjacent cells. The change of leucine to proline is likely to alter the structure of the first TMH of connexin by inducing a kink, thus influencing connexon structure and function.

Erythrokeratodermia variabilis (EKV) is an autosomal dominant keratinization disorder characterized by migratory erythematous lesions and fixed keratotic 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 but not all families. We studied eight affected and three healthy subjects in an Israeli family, of Kurdish origin, with EKV. After having mapped the disorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37. Further investigation revealed a heterozygous T-->C transition leading to the missense mutation (F137L) in the human gene for Cx30.3 that colocalizes on chromosome 1p34-p35. This nucleotide change cosegregated with the disease and was not found in 200 alleles from normal individuals. This mutation concerns a highly conserved phenylalanine, in the third transmembrane region of the Cx30.3 molecule, known to be implicated in the wall 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 heterogeneity of this disorder. Furthermore, we suggest that our family presents a new type of EKV because of the hitherto unreported association with erythema gyratum repens.

A case of 'peeling skin syndrome' is reported. We have demonstrated a hitherto unreported keratohyalin abnormality and a four-fold increase of cellular retinoic acid binding protein, in one of two biopsies from an erythematous, scaling lesion.

The prevalence of keratosis pilaris and accentuated palmoplantar marking was evaluated in 61 patients with atopic dermatitis, 35 patients with dominant ichthyosis vulgaris and 247 other dermatological cases taken as controls. Our data showed that (1) these features are of no diagnostic significance for atopic dermatitis and (2) they are significantly more frequent in patients with ichthyosis vulgaris without associated eczema than in those with atopic dermatitis. Consequently, they should be considered as part of the phenotype of ichthyosis vulgaris rather than attributed to a concomitant atopic dermatitis as suggested by some. These findings should be taken into account when evaluating atopic dermatitis or ichthyosis. To assess the frequency of scaling under winter weather conditions, 155 control subjects were also examined for evidence of visible desquamation and 25.8% showed slight but definite scaling.