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

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Abstract

Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris 1and convey major genetic risk for atopic dermatitis (eczema)2-4, eczema-associated asthma2,3 and other allergic phenotypes 5′. Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of ∼9% in Europe4. 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 - 2009 May 1

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ASJC Scopus subject areas

  • Genetics

Cite this

Fallon, P. G., Sasaki, T., Sandilands, A., Campbell, L. E., Saunders, S. P., Mangan, N. E., Callanan, J. J., Kawasaki, H., Shiohama, A., Kubo, A., Sundberg, J. P., Presland, R. B., Fleckman, P., Shimizu, N., Kudoh, J., Irvine, A. D., Amagai, M., & McLean, W. H. I. (2009). A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nature genetics, 41(5), 602-608. https://doi.org/10.1038/ng.358