Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Frances J. D. Smith, Alan D. Irvine, Ana Terron-Kwiatkowski, Aileen Sandilands, Linda E. Campbell, Yiwei Zhao, Haihui Liao, Alan T. Evans, David R. Goudie, Sue Lewis-Jones, Gehan Arseculeratne, Colin S. Munro, Ann Sergeant, Grainne O'Regan, Sherri J. Bale, John G. Compton, John J. DiGiovanna, Richard B. Presland, Philip Fleckman, W. H. Irwin McLean

    Research output: Contribution to journalArticlepeer-review

    734 Citations (Scopus)

    Abstract

    Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren1. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

    Original languageEnglish
    Pages (from-to)337-342
    Number of pages6
    JournalNature Genetics
    Volume38
    Issue number3
    DOIs
    Publication statusPublished - 2006

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