Recessive Epidermolytic Hyperkeratosis Caused by a Previously Unreported Termination Codon Mutation in the Keratin 10 Gene Patrick Terheyden, Gundula.

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Recessive Epidermolytic Hyperkeratosis Caused by a Previously Unreported Termination Codon Mutation in the Keratin 10 Gene Patrick Terheyden, Gundula Grimberg, Ingrid Hausser, Christian Rose, Bernhard P. Korge, Thomas Krieg, Meral J. Arin Journal of Investigative Dermatology Volume 129, Issue 11, Pages 2721-2723 (November 2009) DOI: 10.1038/jid.2009.131 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical presentation, ultrastructural and immunofluorescence analysis in recessive EH. (a) The affected girl is the second child of consanguineous parents. The simplified pedigree shows several lines of blood relations within the parental families. The parents as well as the brother do not show any skin disease. (b) The clinical presentation at birth was reminiscent of a collodion baby. (c) Histopathology is typical of epidermolytic hyperkeratosis (EH) with suprabasal cytolysis. Magnification × 100. Bar=100μm. (d) Electron microscopy of the granular layer reveals two distinct aggregates within keratinocytes: keratin clumps (KC) and more electron dense keratohyalin granules (KHG). Bar=2.5μm. (e) Immunohistology shows absence of epidermal K10 protein in the affected girl. Normal control (f). Bar=100μm. Journal of Investigative Dermatology 2009 129, 2721-2723DOI: (10.1038/jid.2009.131) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Molecular basis of recessive EH in the present family. (a) Direct sequencing revealed a homozygous nonsense mutation in exon 6 of KRT10 in the affected individual, whereas the unaffected family members are heterozygous carriers of the mutation. The insertion mutation results in a frameshift mutation and a premature termination codon (TGA) six amino acids downstream (p.Lys439fsX6). (b) Quantitative real-time PCR analysis shows a significant decrease of specific KRT10 mRNA in the skin of the homozygous patient compared with a normal control. Levels of the heterozygous father were about 50% of wild type. The data are presented as the fold change in KRT10 mRNA level normalized to the S26 mRNA. The difference in expression of KRT10 mRNA between wild type and recessive Epidermolytic hyperkeratosis (EH) was statistically significant (*P<0.05). Depicted are means and SEM of three experiments. (c) All mutations reported to date in recessive EH (present mutation, p.Lys439fsX6, together with both previously reported mutations, p.Gln434X (Müller et al., 2006) and p.Cys427X (Tsubota et al., 2008)) are located in close proximity at the end of the 2B domain of K10, just upstream of the highly conserved helix termination peptide (red area). The mutation “hotspots” of autosomal dominant EH are depicted in red. The color version of this figure is available on the html full text version of the manuscript. Journal of Investigative Dermatology 2009 129, 2721-2723DOI: (10.1038/jid.2009.131) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions