A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming

Padraic G. Fallon, Takashi Sasaki, Aileen Sandilands, Linda E. Campbell, Sean P. Saunders, Niamh E. Mangan, John J. Callanan, Hiroshi Kawasaki, Aiko Shiohama, Akiharu Kubo, John P. Sundberg, Richard B. Presland, Philip Fleckman, Nobuyoshi Shimizu, Jun Kudoh, Alan D. Irvine, Masayuki Amagai, W. H. Irwin McLean (Lead / Corresponding author)

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    339 Citations (Scopus)

    Abstract

    Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris(1) and convey major genetic risk for atopic dermatitis (eczema)(2-4), eczema-associated asthma(2,3) and other allergic phenotypes(5). Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of similar to 9% in Europe(4). Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate flaky tail as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.

    Original languageEnglish
    Pages (from-to)602-608
    Number of pages7
    JournalNature Genetics
    Volume41
    Issue number5
    DOIs
    Publication statusPublished - May 2009

    Keywords

    • OF-FUNCTION MUTATIONS
    • ATOPIC-DERMATITIS
    • ICHTHYOSIS VULGARIS
    • FILAGGRIN MUTATIONS
    • HUMAN PROFILAGGRIN
    • MICE
    • EXPRESSION
    • DISEASE
    • ASTHMA
    • ECZEMA

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