title: Identification of a de novo keratin 1 mutation in epidermolytic hyperkeratosis with palmoplantar involvement.
abstract: Epidermolytic hyperkeratosis (EHK) (OMIM 113800) is a generalized skin disease with mostly autosomal dominant inheritance, caused by mutations in keratin 1 or keratin 10. These genes are expressed in suprabasal epidermal layers, resulting in abnormal keratin-intermediate filament cytoskeleton. We present a male patient with generalized hyperkeratosis involving palms and soles. In lesional skin massive hyperkeratosis and cytolysis in the suprabasal layers of the epidermis were observed. Immunohistochemistry staining for keratin 1 (and keratin 10) showed abnormal clumping in suprabasal keratinocytes. By electron microscopy perinuclear intermediate filament clumps were detected in the keratinocytes. A heterozygous missense mutation, designated L187F, was identified in exon 1 of the keratin 1 gene by direct sequencing. This mutation was not detected in his unaffected parents, indicative of a de novo mutational event. The homologous mutation (L187F, also designated L7F) in basal keratin genes keratin 5 or -14 causes epidermolysis bullosa simplex. The amount of keratin 1-mRNA in the patient's skin was not altered compared to controls. We propose that the severe EHK phenotype observed in our patient results from a dominant negative effect of the L187F mutant Keratin 1 allele exerted on keratin 10, the associated partner-keratin. These findings should be helpful for genetic counseling, prenatal diagnosis and studying molecular structure-function relationship in EHK.
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Math
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.forename: Alessandra
authors.initials: A
authors.lastname: Handisurya
authors.forename: Pamela
authors.initials: P
authors.lastname: Poblete-Gutiérrez
authors.forename: Katharina
authors.initials: K
authors.lastname: Slupetzky
authors.forename: Dagmar
authors.initials: D
authors.lastname: Födinger
authors.forename: Dorian
authors.initials: D
authors.lastname: Winter
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kirnbauer
mesh_terms: D000328:Adult; D006801:Humans; D017488:Hyperkeratosis, Epidermolytic / Q000235:genetics* / Q000473:pathology; D053556:Keratin-1 / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D053556:Keratin-1; D012333:RNA, Messenger