Letter abstract
Nature Genetics 41, 602 - 608 (2009)
Published online: 6 April 2009 | doi:10.1038/ng.358
A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming
Padraic G Fallon1, Takashi Sasaki2,3, Aileen Sandilands4, Linda E Campbell4, Sean P Saunders1, Niamh E Mangan1, John J Callanan5, Hiroshi Kawasaki6, Aiko Shiohama2,3, Akiharu Kubo6, John P Sundberg7, Richard B Presland8,9, Philip Fleckman9, Nobuyoshi Shimizu3, Jun Kudoh2,3, Alan D Irvine1,10, Masayuki Amagai6,11 & W H Irwin McLean4,11
Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris1 and convey major genetic risk for atopic dermatitis (eczema)2, 3, 4, eczema-associated asthma2, 3 and other allergic phenotypes5. 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.
- Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
- Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
- Advanced Research Center for Genome Super Power, Keio University, Ibaraki, Japan.
- Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, UK.
- Veterinary Sciences Centre, Conway Institute of Biomolecular and Biomedical Research, College of Life Sciences, University College Dublin, Dublin, Ireland.
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
- The Jackson Laboratory, Bar Harbor, Maine, USA.
- Department of Oral Biology, School of Dentistry, University of Washington, Seattle, Washington, USA.
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA.
- Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
- These authors contributed equally to this work.
Correspondence to: W H Irwin McLean4,11 e-mail: w.h.i.mclean@dundee.ac.uk
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