Novel mechanism of revertant mosaicism in Dowling-Meara epidermolysis bullosa simplex

Frances Smith, Susan Morley, Irwin McLean

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    Abstract

    The severe Dowling-Meara form of epidermolysis bullosa simplex is caused by dominant-negative mutations in keratins 5 and 14, which are specifically expressed in the basal keratinocytes of the epidermis. The most common mutation in the Dowling-Meara form of epidermolysis bullosa simplex patients is the missense mutation R125C in exon 1 of the K14 gene. We made a primary keratinocyte cell line from a sporadic case known to carry the R125C mutation as part of an ongoing gene therapy initiative. The full-length K14 cDNA was sequenced using keratinocyte mRNA. Unexpectedly, a second mutation was identified in K14: a heterozygous 1 bp insertion mutation (242insG) upstream of the R125C mutation. This frameshift mutation creates a premature termination codon immediately downstream, thereby nullifying the dominant-negative allele. The second mutation was only present in DNA derived from keratinocytes and was absent from lymphocyte DNA. This case represents a novel mechanism of revertant mosaicism and is an example of "natural gene therapy".
    Original languageEnglish
    Pages (from-to)73-77
    Number of pages5
    JournalJournal of Investigative Dermatology
    Volume122
    Issue number1
    DOIs
    Publication statusPublished - 2004

    Keywords

    • Gene therapy
    • Genodermatosis
    • K14
    • Keratins
    • Mutation

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