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

Abstract

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-

A new type of erythrokeratoderma

“…1 Erythrokeratodermas can be associated with sensorineural deafness and are caused by mutations in the gap junction proteins connexin 30.3 and 31. 2,3 Keratitis-ichthyosis-deafness ⁄hystrix-like ichthyosis-deafness syndrome is caused by mutations in GJB2 (connexin 26) and should also be grouped with the erythrokeratodermas. 4-6 Cases have been described without mutations in any of these genes.…”

A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families

“…Four genes causing deafness (GJB1 (Cx32), GJB2 (Cx26), GJB3 (Cx31) and GJB6 (Cx30)) encode connexin proteins (http://www.iro.es/deafness) and distinct dominant mutations in three of these genes (GJB3, GJB2 and GJB6) are involved in skin diseases (reviewed in Kelsell et al, 2001 andRichard et al, 2000). Recently a mutation (F137L) in GJB4 (MIM# 605425) has been identified in affected members of a family with erythrokeratodermia variabilis (EKV; MIM#1 33200) (Macari et al, 2000) but the role of GJB4 in skin disorders has to be confirmed with the identification of additional EKV families with GJB4 mutations. Furthermore it is unknown whether, as in other epidermal disease-associated connexins, GJB4 mutations also result in hearing impairment.…”

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

“…5,6 Autosomal dominant EKV has been mapped to a single genetic locus on human chromosome 1p34-p35.1 harbouring a cluster of four connexin genes encoding the gap junction proteins Cx30.3 (GJB4), Cx31 (GJB3), Cx31.1 (GJB5) and Cx37 (GJA4). [7][8][9] In the majority of patients, EKV is caused by heterozygous missense mutations in two different connexin genes, GJB3 and GJB4. 4,8,10 Both genes are expressed in the upper spinous and granular layers of the epidermis and are thought to take part in the intercellular communication of keratinocytes.…”

“…[7][8][9] In the majority of patients, EKV is caused by heterozygous missense mutations in two different connexin genes, GJB3 and GJB4. 4,8,10 Both genes are expressed in the upper spinous and granular layers of the epidermis and are thought to take part in the intercellular communication of keratinocytes. 11,12 A small number of EKV patients, however, does not carry pathogenic connexin gene mutations and the molecular basis of the disorder in these patients still remains elusive.…”

“…To date, disease-causing mutations have been reported in 18 unrelated EKV patients and families of predominantly Northern European origin. [4][5][6]8,10,16,17 The mutation spectrum included 12 distinct missense mutations, seven in the Cx31 gene GJB3 and five in the Cx30.3 gene GJB4. While two of the GJB3 mutations (L34P and E100K) showed an autosomal recessive inheritance, 5,6 most were autosomal dominantly transmitted.…”