title: Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused by frameshift mutations altering the v2 tail domains of keratin 1 and keratin 5.
abstract: The cytoskeleton of epithelial cells is formed by heteropolymeric keratin proteins characterized by a central alpha-helical rod flanked by nonhelical head and tail domains of variable sequence. Most mutations described in 18 distinct keratins disrupt highly conserved regions at the boundaries of the rod, which have been recognized as zones of overlap during keratin alignment and assembly into intermediate filaments. We recently reported the first mutation located in a keratin tail domain (V2) in ichthyosis hystrix Curth-Macklin. In this study, we report two novel frameshift mutations that are predicted to alter the tail of keratin 1 or keratin 5, leading to an atypical form of epidermolytic hyperkeratosis and a mild form of epidermolysis bullosa simplex, respectively. Mutation analysis of the patient with epidermolytic hyperkeratosis revealed a de novo heterozygous nucleotide insertion (1752insG) in exon 9 of KRT1, predicted to result in an aberrant 69 residue keratin 1 tail. In the patient with mild epidermolysis bullosa simplex, we identified a single nucleotide deletion (1635delG) in exon 9 of KRT5 leading to frameshift and translation of an abnormal V2 domain, 35 amino acids longer than the native keratin 5 tail. Our results, together with previous observations, establish the existence of a subgroup of keratin disorders due to frameshift mutations altering the keratin tail domains that are characterized by phenotypic heterogeneity.
authors.affiliation: Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa, Israel. e_sprecher@rambam.health.gov.il
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Gil
authors.initials: G
authors.lastname: Yosipovitch
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.forename: Dan
authors.initials: D
authors.lastname: Ciubutaro
authors.forename: Margarita
authors.initials: M
authors.lastname: Indelman
authors.forename: Ellen
authors.initials: E
authors.lastname: Pfendner
authors.forename: Leok C
authors.initials: LC
authors.lastname: Goh
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics*; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006801:Humans; D017488:Hyperkeratosis, Epidermolytic / Q000235:genetics*; D053555:Keratin-5; D007633:Keratins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: C503940:KRT5 protein, human; D053555:Keratin-5; D007633:Keratins