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European Journal of Dermatology

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Identification of a de novo keratin 1 mutation in epidermolytic hyperkeratosis with palmoplantar involvement Volume 16, issue 5, September-October 2006

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Authors
Division of Immunology, Allergy and Infectious Diseases (DIAID), Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Division of Special and Environmental Dermatology Medical University of Vienna, Vienna, Austria, Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria, Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands, Maasticht University Center for Molecular Dermatology (MUCMD)

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.