title: A mutation (N177S) in the structurally conserved helix initiation peptide motif of keratin 5 causes a mild EBS phenotype.
abstract: Epidermolysis bullosa simplex (EBS) is a group of predominantly autosomal dominant hereditary disorders of the skin, which manifest as superficial skin blisters after minimal mechanical trauma. Three subtypes have been defined, based on clinical severity. Mutations affecting the genes encoding the epidermal keratins 5 (K5) and 14 (K14) have been linked to the disease, and generally those affecting the helix initiation and termination peptide motifs have been linked to severe EBS phenotypes. We report here a novel mutation in the helix initiation peptide of K5, N177S, that causes only a mild EBS-Weber Cockayne phenotype (EBS-WC). The mutation was identified by direct sequencing of polymerase chain reaction (PCR)-amplified genomic DNA encoding the exons of the KRT5 and KRT14 genes, and confirmed by mismatch allele-specific PCR, followed by restriction enzyme digestion with Tsp509 I. The patient is heterozygous for a mutation affecting codon 177, changing a conserved asparagine residue (N) to serine (S). Asparagine 177 is a highly conserved residue among all type II keratins. This is also the first report of a mutation at position 9 of 1A helix (1A:N9S) in a type II keratin. Unlike mutations affecting residues 4, 5, 7, 8, 10, and 11 of the 1A helix of K5 and K14, which were all previously linked to more severe (EBS) phenotypes, K5 1A:N9S produces only a mild EBS-WC phenotype.
authors.affiliation: Medical Centre for Molecular Biology, University of Ljubljana, Ljubljana, Slovenia. m.viovic@dundee.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Liovic
authors.forename: P E
authors.initials: PE
authors.lastname: Bowden
authors.forename: R
authors.initials: R
authors.lastname: Marks
authors.forename: R
authors.initials: R
authors.lastname: Komel
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs / Q000235:genetics; D001216:Asparagine / Q000235:genetics; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D053555:Keratin-5; D007633:Keratins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012694:Serine / Q000235:genetics
chemical_list: C503940:KRT5 protein, human; D053555:Keratin-5; D012694:Serine; D007633:Keratins; D001216:Asparagine; D004247:DNA