Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Abstract

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades1 and now affects 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable2. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated3. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pedigrees of the nine families studied with semidominant inheritance of ichthyosis vulgaris and atopic dermatitis ('eczema').
Figure 2: Filaggrin variants represent a substantial fraction of individuals with asthma and atopic dermatitis (AD).

References

  1. Holgate, S.T. The epidemic of allergy and asthma. Nature 402, B2–B4 (1999).

    Article  CAS  Google Scholar 

  2. Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002).

    Article  CAS  Google Scholar 

  3. Cookson, W.O. & Moffatt, M.F. The genetics of atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 2, 383–387 (2002).

    Article  Google Scholar 

  4. Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 6, 328–340 (2005).

    Article  CAS  Google Scholar 

  5. Listwan, P. & Rothnagel, J.A. Keratin bundling proteins. Methods Cell Biol. 78, 817–827 (2004).

    Article  CAS  Google Scholar 

  6. Gan, S.Q., McBride, O.W., Idler, W.W., Markova, N. & Steinert, P.M. Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry 29, 9432–9440 (1990).

    Article  CAS  Google Scholar 

  7. Presland, R.B. & Dale, B.A. Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit. Rev. Oral Biol. Med. 11, 383–408 (2000).

    Article  CAS  Google Scholar 

  8. Compton, J.G., DiGiovanna, J.J., Johnston, K.A., Fleckman, P. & Bale, S.J. Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1. Exp. Dermatol. 11, 518–526 (2002).

    Article  CAS  Google Scholar 

  9. Smith, F.J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–342 (2006).

    Article  CAS  Google Scholar 

  10. Bisgaard, H. The Copenhagen prospective study on asthma in childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann. Allergy Asthma Immunol. 93, 381–389 (2004).

    Article  Google Scholar 

  11. Masoli, M., Fabian, D., Holt, S. & Beasley, R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478 (2004).

    Article  Google Scholar 

  12. Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112, S118–S127 (2003).

    Article  Google Scholar 

  13. Tabata, N., Tagami, H. & Kligman, A.M. A twenty-four-hour occlusive exposure to 1% sodium lauryl sulfate induces a unique histopathologic inflammatory response in the xerotic skin of atopic dermatitis patients. Acta Derm. Venereol. 78, 244–247 (1998).

    Article  CAS  Google Scholar 

  14. Seguchi, T. et al. Decreased expression of filaggrin in atopic skin. Arch. Dermatol. Res. 288, 442–446 (1996).

    Article  CAS  Google Scholar 

  15. Jensen, J.M. et al. Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J. Invest. Dermatol. 122, 1423–1431 (2004).

    Article  CAS  Google Scholar 

  16. Sugiura, H. et al. Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br. J. Dermatol. 152, 146–149 (2005).

    Article  CAS  Google Scholar 

  17. Cookson, W.O. et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat. Genet. 27, 372–373 (2001).

    Article  CAS  Google Scholar 

  18. Wells, R.S. & Kerr, C.S. Clinical features of autosomal dominant and sex-linked ichthyosis in an English Population. Br. Med. J. 1, 947–950 (1966).

    Article  CAS  Google Scholar 

  19. Kuokkanen, K. Ichthyosis vulgaris. A clinical and histopathological study of patients and their close relatives in the autosomal dominant and sex-linked forms of the disease. Acta Derm. Venereol. Suppl. (Stockh.) 62, 1–72 (1969).

    CAS  Google Scholar 

  20. Tay, Y.K., Khoo, B.P. & Goh, C.L. The epidemiology of atopic dermatitis at a tertiary referral skin center in Singapore. Asian Pac. J. Allergy Immunol. 17, 137–141 (1999).

    CAS  PubMed  Google Scholar 

  21. Wang, L.F., Lin, J.Y., Hsieh, K.H. & Lin, R.H. Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J. Immunol. 156, 4077–4082 (1996).

    CAS  PubMed  Google Scholar 

  22. Spergel, J.M. et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J. Clin. Invest. 101, 1614–1622 (1998).

    Article  CAS  Google Scholar 

  23. Ginger, R.S., Blachford, S., Rowland, J., Rowson, M. & Harding, C.R. Filaggrin repeat number polymorphism is associated with a dry skin phenotype. Arch. Dermatol. Res. 297, 235–241 (2005).

    Article  CAS  Google Scholar 

  24. Kurz, T. et al. A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3. Allergy 60, 192–199 (2005).

    Article  CAS  Google Scholar 

  25. Wuthrich, B. & Schmid-Grendelmeier, P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated (“extrinsic”) and the nonallergic (“intrinsic”) AEDS. J. Investig. Allergol. Clin. Immunol. 13, 1–5 (2003).

    CAS  PubMed  Google Scholar 

  26. Williams, H.C., Burney, P.G., Pembroke, A.C. & Hay, R.J. The U.K. Working Party's diagnostic criteria for atopic dermatitis. III. Independent hospital validation. Br. J. Dermatol. 131, 406–416 (1994).

    Article  CAS  Google Scholar 

  27. Williams, H.C. et al. The U.K. Working Party's diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br. J. Dermatol. 131, 383–396 (1994).

    Article  CAS  Google Scholar 

  28. Emerson, R.M., Charman, C.R. & Williams, H.C. The Nottingham eczema severity score: preliminary refinement of the Rajka and Langeland grading. Br. J. Dermatol. 142, 288–297 (2000).

    Article  CAS  Google Scholar 

  29. Cecil, J.E. et al. The Pro12Ala and C-681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren. Diabetologia 48, 1496–1502 (2005).

    Article  CAS  Google Scholar 

  30. Brydensholt, H.L. et al. Development of atopic dermatitis during the first 3 years of life. The COPSAC cohort study in high-risk children. Arch. Dermatol. (in the press).

Download references

Acknowledgements

We thank the patients and their families for their participation which made this research possible, K. Johnston for clinical assistance, and the following at Ninewells Hospital and Medical School: J. Hands, N. Joy and C. Black, Molecular Genetics Laboratory, for DNA extraction and storage; A. Cassidy, G. Scott and G. McGregor, DNA Analysis Facility, for genotyping support; I. Murrie, T. Ismail, Children's Asthma and Allergy Unit, for field work and data entry and J. Mcfarlane, Epithelial Genetics Group for clerical assistance. We thank M. Greenway, National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland for providing Irish control samples. We thank H. Williams, University of Nottingham, UK for permission to use the Nottingham Eczema Severity Score. This work was supported by a Wellcome Trust Senior Research Fellowship (W.H.I.M.), the Odland Endowed Research Fund (P.F.), as well as grants from the Dystrophic Epidermolysis Bullosa Research Association (W.H.I.M.), the Pachyonychia Congenita Project (F.J.D.S.), the British Skin Foundation/National Eczema Society (F.J.D.S. & W.H.I.M.), the Biotechnology and Biological Sciences Research Council (award D13460; C.N.A.P.), Scottish Enterprise Tayside and the Gannochy Trust (C.N.A.P. and S.M.). C.N.A.P. is also supported by the Scottish Executive Genetic Health Initiative. K. McE. is supported by GIS, Institut des maladies rares. G.M.O'R. is supported by a grant from the Children's Medical and Research Foundation, Our Lady's Hospital for Sick Children, Dublin.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W H Irwin McLean.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Characteristics of atopic dermatitis and asthma subjects with and without FLG variants. (PDF 72 kb)

Supplementary Table 2

Allele frequencies of FLG mutations R501X and 2282del4 in human populations. (PDF 62 kb)

Supplementary Table 3

PCR primers and probes used for genotyping of FLG variants. (PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palmer, C., Irvine, A., Terron-Kwiatkowski, A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38, 441–446 (2006). https://doi.org/10.1038/ng1767

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1767

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing