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PubMed2000

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

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.

Adult↗

PubMed1998

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Amino Acid Sequence↗

PubMed2005

A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis.

BACKGROUND: Erythrokeratodermia variabilis (EKV) is an autosomal dominant or recessive genodermatosis characterized by the coexistence of randomly occurring, transient, erythematous patches and hyperkeratosis of the skin. The disorder has been mapped to chromosome 1p35.1 but is genetically heterogeneous. EKV may be caused by pathogenic mutations in one of two neighbouring connexin genes, GJB3 and GJB4, encoding the gap junction proteins Cx31 and Cx30.3, respectively. Twelve distinct mutations identified to date cluster either at the cytoplasmic amino-terminus or in the four transmembrane domains. OBJECTIVES: To report a large family with EKV and an unrelated sporadic case. METHODS: DNA amplification and mutation analysis, followed by denaturing high-performance liquid chromatography to confirm the segregation of the mutations in the two families with EKV. RESULTS: A novel, recurrent GJB3 mutation (625C-->T; L209F) was identified in the family with EKV and in the unrelated sporadic case. CONCLUSIONS: This mutation is the first to affect a conserved residue in the cytoplasmic carboxy-terminus of any connexin gene with a cutaneous phenotype, emphasizing its structural and/or functional importance.

Adult↗

PubMed1990

Acitretin in the treatment of erythrokeratodermia variabilis.

A patient with erythrokeratodermia variabilis (Mendes da Costa's disease) is presented, and the clinical and histological response to acitretin is described. An initial dose of 35 mg of acitretin and a maintenance dose of 25-35 mg resulted in a pronounced and sustained improvement. Further reduction of the dosage resulted in a relapse within a few days. At the histological level the extensive hyperkeratosis and the moderate dermal inflammatory infiltrate decreased during treatment with acitretin. In comparison with the other retinoids available so far, acitretin is the derivative of first choice in the treatment of erythrokeratodermia variabilis Mendes da Costa.

Acitretin↗

PubMed2003

Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.

Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the etiology of erythrokeratodermia variabilis. In this study, we sequenced the coding region of GJB4 in 13 unrelated erythrokeratodermia variabilis families without detectable mutations in GJB3. Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls. Mutation G12D, identified in an extended Dutch family, lies in the predicted amino-terminus and may interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. Affected individuals of two unrelated families harbored point mutations leading to amino acid substitution F137L, which was also reported in GJB3, yet the extent and severity of hyperkeratosis was milder compared to the corresponding mutation in GJB3. Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects. Nevertheless, we observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region, which might represent either inconsequential polymorphisms or recessive mutations. In conclusion, our results demonstrate genetic heterogeneity in erythrokeratodermia variabilis, and emphasize that intercellular communication mediated by both Cx31 and Cx30.3 is crucial for epidermal differentiation.

Connexins↗

PubMed1978

Erythrokeratodermia variabilis. A family study.

Erythrokeratodermia variabilis is a rare genodermatosis; American authors have reported only four previous cases. It had been a problem to obtain a large pedigree for clinical investigation. We studied a family with 12 involved members in five generations. Symmetrically distributed migratory patches and scaling plaques are characteristic and were found to involute with a combination of keratolytic agents and topical steroids. Exacerbations of these patches and plaques were noted in our female patients during such high estrogen states as pregnancy or oral contraceptive usage.

Adult↗

PubMed1985

[A case of erythrokeratodermia variabilis].

A case of erythrokeratodermia variabilis in a 7.5-years-old girl with transient achromic lesions and nail changes is described. Histologically peculiar eosinophilic formations with nuclear remnants in the stratum corneum were found. The mother and the grandfather only had hyperkeratotic lesions on the soles.

Child↗

PubMed1988

Further evidence for localization of the gene of erythrokeratodermia variabilis.

Close genetic linkage between erythrokeratodermia variabilis (EKV) and the Rh blood group system has been reported by our group. Here we describe the results of a linkage analysis in another EKV kindred, in which the disease segregated with the CDe genotype. Among 18 informative individuals, 1 recombinant was found. A maximum lod score of 4.21 was calculated at a recombination fraction of 0.03-0.04. Addition of this lod score to the earlier reported results gives a maximum lod score of 9.93 for linkage between EKV and Rh at a recombination fraction of 0.03 (95% confidence limits 0.008-0.11).

Female↗

PubMed2004

An atypical form of erythrokeratodermia variabilis maps to chromosome 7q22.

Erythrokeratodermia variabilis 3 (Kamouraska type) or EKV3 is a newly described autosomal recessive disorder observed in patients from the Bas St-Laurent region of Quebec. It has similar skin lesions as observed for EKV, including congenital hyperkeratosis and red patches of variable sizes, shapes, and duration. EKV3 is also characterized by ichthyosis, sensorineural hearing loss, peripheral neuropathy, psychomotor retardation, congenital chronic diarrhea, and an elevation of very long chain fatty acids (VLCFAs). To map the disease locus, we performed candidate gene analysis and a genomewide scan to identify a common homozygous region in affected individuals from three non-consanguineous families. Mutations in connexin 31 (GJB3) and connexin 30.3 (GJB4), implicated in previous reports of EKV, and connexin 26 (GJB2), implicated in palmoplantar keratoderma, were unlikely given the lack of shared homozygous haplotypes in the regions surrounding these genes. The most promising region of common homozygosity observed in a 4,600 single-nucleotide polymorphism genome scan was further characterized by using microsatellites. A 6.8-Mb region on chromosome 7 between D7S2539 and rs727708 was found to be homozygous for the same haplotype in all affected individuals but not in the parents or an unaffected sibling. This region contains connexin 31.3 (GJE1), and although no mutation have been observed in the coding region of this gene, further analyses are required in order to exclude it. Identification of the gene responsible for this disorder will provide insights into the etiology of this multisystemic disorder.

Chromosomes, Human, Pair 7↗

PubMedDate not supplied

Erythrokeratodermia variabilis with erythema gyratum repens-like lesions.

A large pedigree with erythrokeratodermia variabilis (EKV) and erythema gyratum repens-like lesions is described. Clinical, laboratory, and histologic findings of this family are presented. The differential diagnoses of the following dermatoses with an erythematous and a hyperkeratotic component are discussed: erythrokeratodermia variabilis (Mendes da Costa), progressive symmetric erythrokeratoderma (Gottron), loricrin keratoderma, erythrokeratoderma en cocardes (Degos), Netherton syndrome, keratitis-ichthyosis-deafness (KID) syndrome, erythrokeratolysis hiemalis (Oudtshoorn disease), and nonbullous congenital ichthyosiform erythroderma.

Adult↗

PubMedDate not supplied

Acitretin for erythrokeratodermia variabilis in a 9-year-old girl.

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis with a unique phenotype. Treatment with oral synthetic retinoids is well documented in adults, but not in children. We report a 9-year-old girl with EKV who cleared rapidly following treatment with oral acitretin.

Acitretin↗

PubMed2002

Expression of a connexin31 mutation causing erythrokeratodermia variabilis is lethal for HeLa cells.

The autosomal dominant skin disorder erythrokeratodermia variabilis (EKV) has been linked to mutations in the human connexin31 (hCx31) gene, which is expressed in the epidermis. We characterized and compared a pathogenic mutation resulting in replacement of amino acid glycine 12 with arginine (G12R) with wild-type hCx31 protein. HeLa cells were transfected with wild-type and mutant hCx31 cDNA, respectively, using different-constitutive and inducible-vector systems. Independent of the expression vector, wild-type and mutant hCx31 were expressed at comparative levels and localized at the plasma membranes. Mutated channels (hCx31G12R) showed higher conductance in dye coupling studies than wild type channels. Furthermore, HeLa cells died within 5 days after constitutive expression of the mutant protein. Using an inducible expression system, we demonstrated a direct correlation between survival/life span of transfected HeLa cells and expression level of the mutant protein, indicating a gain-of-function mechanism due to a defective channel closure mechanism.

Amino Acid Substitution↗

PubMed1982

Erythrokeratodermia variabilis in a patient followed through the first year of life.

Erythrokeratodermia variabilis (EKV) is a well-described entity consisting of transient erythematous areas and fixed hyperkeratotic plaques. Here, a white infant girl with EKV consistent with the classic form of the disease and several previously described variants is presented. This patient was first seen at 6 weeks of age and subsequently followed until she was 12 months old.

Erythema↗

PubMed2002

A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.

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.

Amino Acid Sequence↗

PubMed1977

Erythrokeratodermia variabilis.

The case of a 10 year-old Japanese boy with erythrokeratodermia variabilis is reported in addition to a review of the Japanese literature. The patient was first examined in our clinic on October 21, 1965, because of generalized hyperkeratotic lesions and erythematous lesions which had persisted since he was 3 months old. Hyperkeratotic and verrucous lesions were noted on his auricles and trunk, on which there were also sharply demarcated erythematous lesions of various sizes and shapes which were not elevated from the adjacent skin. Laboratory findings were within normal limits. Histopathological examination revealed a remarkable hyperkeratosis with a basket weave appearance, moderate acanthosis and a slightly thickened granular layer. Polyethylenglycol 400 and corticosteroid ointment were slightly beneficial to the hyperkeratotic lesions.

Biopsy, Needle↗

PubMed2006

Erythrokeratodermia variabilis with adult onset: report of a sporadic case unresponsive to systemic retinoids.

Erythrokeratodermia variabilis is a rare autosomal-dominant genodermatosis characterized by migratory and erythematous patches changing over the course of hours to days, and fixed keratotic plaques. The disease begins mostly at birth or within the first year of life; it very rarely starts after childhood. We present herein a sporadic case with adult onset that was unusually resistant to both isotretinoin and acitretin.

Acitretin↗

PubMed2005

[Erythrokeratodermia variabilis (EKV)--a disorder due to altered epidermal expression of gap junction proteins].

Erythrokeratodermia variabilis (EKV) is a rare autosomal dominant genodermatosis with disturbed epidermal differentiation. Its clinical picture varies from transient, fast moving erythema to persistent brown hyperkeratoses. The gene defect in EKV was recently located on the short arm of chromosome 1 encoding the gap junction protein connexin 31. We report on a 48-year-old patient with sharply circumscribed, scaling erythema on the extremities, buttocks and trunk starting since 30 years of age. Histological investigation showed orthokeratotic hyperkeratosis with focal parakeratosis overlying an acanthotic epidermis. Immunohistochemistry revealed a decreased expression of the gap junction protein connexin 31 as well as increased expression of connexin 43. At the ultrastructural level, widened intercellular spaces in the upper epidermis were present with regular desmosomes, adherens junctions and gap junctions. Epidermal cell proliferation and differentiation are regulated by gap junctions. The mutation in connexin 31 is regarded therefore as causal for the clinical picture of the EKV. The unique upregulation of connexin 43 may occur as a consequence of the Cx31 mutation and temporarily compensate for this defect.

Acitretin↗

PubMed1978

Erythrokeratodermia variabilis in a Jewish Kurdish family.

A Jewish family, originating from Kurdistan and presenting erythrokeratodermia variabilis in three consecutive generations, is described. The major features were the variable age of onset (from early infancy to 6 years) and the distinctive cutaneous lesions with demarcated erythematous hyperkeratotic plaques with irregular borders. The affected members had mild to severe expressions of the disease. The skin lesions were not influenced by puberty, pregnancy or old age. None of the patients had lesions of the palms and soles or abnormal neurological signs.

Adult↗