A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming (original) (raw)

• Letter
• Published: 06 April 2009
• 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 na1 &
• …
• W H Irwin McLean4 na1

Nature Genetics volume 41, pages 602–608 (2009)Cite this article

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Abstract

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.

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Acknowledgements

We thank B. Mistry, A. Smyth, T. Adachi and M. Furuhashi for their technical assistance and T. Yoshida for his cooperation. We are grateful for the assistance of B. Cloak with photomicrography and S. Worrell with histopathology. This work was supported by the Labour Sciences Research Grants for Research on Allergic Disease and Immunology from the Ministry of Health, Labour, and Welfare of Japan (M.A.), National Institute of Health grants P01 AM21557 (P.F.), R01 AR49183 (R.B.P.) and the Odland Endowed Research Fund (P.F.). P.G.F. was supported by Science Foundation Ireland. A.D.I. is supported by the Children's Medical and Research Foundation, OLCHC. Filaggrin research in the McLean laboratory is supported by grants from The British Skin Foundation, The National Eczema Society, The Medical Research Council (Reference number G0700314) and donations from anonymous families affected by eczema in the Tayside Region of Scotland.

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Author notes

1. Masayuki Amagai and W H Irwin McLean: These authors contributed equally to this work.

Authors and Affiliations

1. Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
   Padraic G Fallon, Sean P Saunders, Niamh E Mangan & Alan D Irvine
2. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
   Takashi Sasaki, Aiko Shiohama & Jun Kudoh
3. Advanced Research Center for Genome Super Power, Keio University, Ibaraki, Japan
   Takashi Sasaki, Aiko Shiohama, Nobuyoshi Shimizu & Jun Kudoh
4. Division of Molecular Medicine, Epithelial Genetics Group, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, UK
   Aileen Sandilands, Linda E Campbell & W H Irwin McLean
5. Veterinary Sciences Centre, Conway Institute of Biomolecular and Biomedical Research, College of Life Sciences, University College Dublin, Dublin, Ireland
   John J Callanan
6. Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
   Hiroshi Kawasaki, Akiharu Kubo & Masayuki Amagai
7. The Jackson Laboratory, Bar Harbor, Maine, USA.,
   John P Sundberg
8. Department of Oral Biology, School of Dentistry, University of Washington, Seattle, Washington, USA
   Richard B Presland
9. Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA
   Richard B Presland & Philip Fleckman
10. Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
    Alan D Irvine

Authors

1. Padraic G Fallon
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2. Takashi Sasaki
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3. Aileen Sandilands
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4. Linda E Campbell
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5. Sean P Saunders
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6. Niamh E Mangan
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7. John J Callanan
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8. Hiroshi Kawasaki
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9. Aiko Shiohama
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10. Akiharu Kubo
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11. John P Sundberg
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12. Richard B Presland
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13. Philip Fleckman
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14. Nobuyoshi Shimizu
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15. Jun Kudoh
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16. Alan D Irvine
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17. Masayuki Amagai
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18. W H Irwin McLean
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Contributions

The study was designed by W.H.I.M., P.G.F., A.D.I and M.A. Molecular biology was performed by T.S., A. Sandilands, L.E.C., H.K., A. Shiohama, A.K., N.S. and J.K. Bioinformatics was performed by W.H.I.M. C-terminal profilaggrin antibody and immunoblot data was generated by R.B.P. and P.F. The initial mixed strain ft mice were provided by J.P.S. Mouse backcrossing, immunology and histological experiments were performed by P.G.F., S.P.S., N.E.M and J.J.C. The manuscript was written by P.G.F., T.S., J.K., M.A., R.B.P., A.D.I. and W.H.I.M.

Corresponding author

Correspondence toW H Irwin McLean.

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Fallon, P., Sasaki, T., Sandilands, A. et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet 41, 602–608 (2009). https://doi.org/10.1038/ng.358

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• Received: 11 September 2008
• Accepted: 18 February 2009
• Published: 06 April 2009
• Issue Date: May 2009
• DOI: https://doi.org/10.1038/ng.358

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