title: A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.
abstract: 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.
authors.affiliation: Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gottfried
authors.forename: Marina
authors.initials: M
authors.lastname: Landau
authors.forename: Fabian
authors.initials: F
authors.lastname: Glaser
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Di
authors.forename: Joseph
authors.initials: J
authors.lastname: Ophir
authors.forename: Barukh
authors.initials: B
authors.lastname: Mevorah
authors.forename: Nir
authors.initials: N
authors.lastname: Ben-Tal
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004890:Erythema / Q000235:genetics*; D017629:Gap Junctions / Q000502:physiology; D005808:Genes, Recessive; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D007642:Keratosis / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D021381:Protein Transport; D016415:Sequence Alignment
chemical_list: D017630:Connexins; C068044:GJB3 protein, human