Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused by frameshift mutations altering the V2 tail domains of keratin 1 and keratin 5

Eli Sprecher, Gil Yosipovitch, Reuven Bergman, Dan Ciubutaro, Margarita Indelman, Ellen Pfendner, Leok C. Goh, Christopher J. Miller, Jouni Uitto, Gabriele Richard

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The cytoskeleton of epithelial cells is formed by heteropolymeric keratin proteins characterized by a central α-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 hyper-keratosis 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.

Original languageEnglish (US)
Pages (from-to)623-626
Number of pages4
JournalJournal of Investigative Dermatology
Volume120
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Keywords

  • Epidermolysis bullosa simplex
  • Epidermolytic hyperkeratosis
  • Keratin intermediate filament
  • Palmoplantar keratoderma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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