A Large Mutational Study in Pachyonychia Congenita

Neil J. Wilson, Sancy A. Leachman, C. David Hansen, Alexandra C. McMullan, Leonard M. Milstone, Mary E. Schwartz, W. H. Irwin McLean, Peter R. Hull, Frances J. D. Smith

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    Abstract

    Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.

    Original languageEnglish
    Pages (from-to)1018-1024
    Number of pages7
    JournalJournal of Investigative Dermatology
    Volume131
    Issue number5
    DOIs
    Publication statusPublished - May 2011

    Keywords

    • EPIDERMOLYSIS-BULLOSA SIMPLEX
    • FOCAL PALMOPLANTAR KERATODERMA
    • DOWLING-DEGOS-DISEASE
    • ICHTHYOSIS HYSTRIX
    • SIZE POLYMORPHISM
    • CLOUSTON-SYNDROME
    • KERATIN-5
    • FAMILY
    • TYPE-2
    • HYPERKERATOSIS

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