title: Mutation S233L in the 1B domain of keratin 1 causes epidermolytic palmoplantar keratoderma with "tonotubular" keratin.
abstract: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis restricted to the palm and sole epidermis. The disorder is normally associated with dominant-negative mutations in the keratin 9 (K9) gene; however, a small number of cases have been reported where causative mutations were identified in the K1 gene. Here, we present two unrelated Dutch EPPK families with striking ultrastructural findings: tubular keratin structures in the cytoplasm of suprabasal cells. Similar structures were reported previously in a German EPPK family and were termed "tonotubular" keratin. After excluding the involvement of the K9 gene by complete sequencing, we identified a novel mutation, S233L, at the beginning of the 1B domain of K1 in both families. Protein expression studies in cultured cells indicated pathogenicity of this mutation. This is the first report of a genetic defect in this domain of K1. The unusual gain-of-function mutation points to a subtle role of the 1B domain in mediating filament-filament interactions with regular periodicity.
authors.affiliation: Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Terron-Kwiatkowski
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: E Birgitte
authors.initials: EB
authors.lastname: Lane
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
mesh_terms: D006801:Humans; D053556:Keratin-1; D007633:Keratins / Q000737:chemistry / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D008854:Microscopy, Electron; D009154:Mutation; D017434:Protein Structure, Tertiary
chemical_list: C491616:KRT1 protein, human; D053556:Keratin-1; D007633:Keratins