Abstract
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris1 and predispose to eczema and secondary allergic diseases2. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (χ2 test: P = 2.12 × 10−51; Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9–11.3), and homozygote OR = 151 (95% c.i. = 20–1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Smith, F.J.D. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–342 (2006).
Palmer, C.N.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).
Judge, M.R., McLean, W.H.I. & Munro, C.S. Disorders of keratinization. in Rook's Textbook of Dermatology Vol. 2 (eds. Burns, T., Breathnach, S., Cox, C. & Griffiths, C.) 34.54–34.56 (Blackwell Scientific, Oxford, 2004).
Sandilands, A. et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J. Invest. Dermatol. 126, 1770–1775 (2006).
Gruber, R. et al. Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris. Eur. J. Hum. Genet. 15, 179–184 (2007).
Barker, J.N. et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J. Invest. Dermatol. 127, 564–567 (2007).
Weidinger, S. et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J. Allergy Clin. Immunol. 118, 214–219 (2006).
Weidinger, S. et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J. Invest. Dermatol. 127, 724–726 (2007).
Ruether, A., Stoll, M., Schwarz, T., Schreiber, S. & Folster-Holst, R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany. Br. J. Dermatol. 155, 1093–1094 (2006).
Marenholz, I. et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immunol. 118, 866–871 (2006).
Stemmler, S., Parwez, Q., Petrasch-Parwez, E., Epplen, J.T. & Hoffjan, S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J. Invest. Dermatol. 127, 722–724 (2006).
Morar, N., Cookson, W.O., Harper, J.I. & Moffatt, M.F. Filaggrin mutations in children with severe atopic dermatitis. J. Invest. Dermatol. advance online publication, 15 February 2007 (doi:10.1038/sj.jid.5700739).
Irvine, A.D. Fleshing out filaggrin phenotypes. J. Invest. Dermatol. 127, 504–507 (2007).
Irvine, A.D. & McLean, W.H.I. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J. Invest. Dermatol. 126, 1200–1202 (2006).
Mischke, D., Korge, B.P., Marenholz, I., Volz, A. & Ziegler, A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21. J. Invest. Dermatol. 106, 989–992 (1996).
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).
Nomura, T. et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J. Allergy Clin. Immunol. 119, 434–440 (2007).
Presland, R.B. et al. Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J. Invest. Dermatol. 115, 1072–1081 (2000).
Rawlings, A.V. & Harding, C.R. Moisturization and skin barrier function. Dermatol. Ther. 17 Suppl 1, 43–48 (2004).
Katagiri, C., Sato, J., Nomura, J. & Denda, M. Changes in environmental humidity affect the water-holding property of the stratum corneum and its free amino acid content, and the expression of filaggrin in the epidermis of hairless mice. J. Dermatol. Sci. 31, 29–35 (2003).
Takahashi, M., Tezuka, T. & Katunuma, N. Filaggrin linker segment peptide and cystatin alpha are parts of a complex of the cornified envelope of epidermis. Arch. Biochem. Biophys. 329, 123–126 (1996).
McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).
Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).
Cookson, W.O. et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat. Genet. 27, 372–373 (2001).
Acknowledgements
We thank affected individuals and their families for their participation, which made this research possible, and J. Mcfarlane (Epithelial Genetics Group) for clerical assistance. The Irvine group is supported by the Children's Medical and Research Foundation of Our Lady's Children's Hospital. The McLean/Smith group is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project and the British Skin Foundation/National Eczema Society (W.H.I.M and F.J.D.S.). The Palmer group is supported by the Biotechnology and Biological Sciences Research Council (award D13460), Scottish Enterprise Tayside and the Gannochy Trust and the Scottish Executive Genetic Health Initiative. The Innsbruck group is supported by the Medical Research Fund of the Innsbruck University Medical Center (Medical Finance Fund numbers 71 and 153) and the Austrian National Bank (Austrian National Bank number 10822).
Author information
Authors and Affiliations
Contributions
The study was designed by W.H.I.M., A.D.I., A.S. and F.J.D.S. The atopic dermatitis case series was collected by A.D.I., G.M.O'R., R.M.W. and T.H.C.; Irish population controls were obtained by D.G.B. and additional clinical contributions were made by P.R.H., C.S.M., M.A.M.v.S., P.M.S., I.N. and M.S. DNA was extracted and stored by L.E.C. Clinical samples and case series were managed by P.R.H. Molecular biology was performed by A.S., A.T.-K., P.R.H., T.C., H.L., Y.Z., L.E.C., M.v.G., A.R.J. and R.G. Histological and ultrastructural work was done by A.T.E., W.H.I.M., M.S. and P.M.E. Statistical analysis was done by C.N.A.P. The manuscript was written by W.H.I.M., A.D.I., A.S., M.S. and F.J.D.S.
Corresponding authors
Ethics declarations
Competing interests
W.H.I.M. and F.J.D.S. have filed patents relating to genetic testing and therapy development aimed at the filaggrin gene.
Supplementary information
Supplementary Fig. 1
Filaggrin priming sites and FLG8+10+ allele. (PDF 579 kb)
Supplementary Fig. 2
PCR strategy and primers for exon 3. (PDF 128 kb)
Supplementary Fig. 3
Pedigrees and mutation data, additional immunohistochemistry and immunoblotting data and electron microscopy. (PDF 414 kb)
Supplementary Table 1
Filaggrin mutations and prevalence data. (PDF 82 kb)
Supplementary Table 2
SNP and microsatellite analysis. (PDF 77 kb)
Supplementary Table 3
Clinical details of atopic dermatitis case series. (PDF 86 kb)
Supplementary Table 4
Primers and probes for mutation screening. (PDF 93 kb)
Rights and permissions
About this article
Cite this article
Sandilands, A., Terron-Kwiatkowski, A., Hull, P. et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 39, 650–654 (2007). https://doi.org/10.1038/ng2020
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng2020
This article is cited by
-
Filaggrin gene variants among Saudi patients with ichthyosis vulgaris
BMC Medical Genomics (2023)
-
Atopic Dermatitis Across Shades of Skin
American Journal of Clinical Dermatology (2023)
-
Epithelial barrier hypothesis and the development of allergic and autoimmune diseases
Allergo Journal International (2022)
-
Epithelial barrier hypothesis and the development of allergic and autoimmune diseases
Allergo Journal (2022)
-
Pyridoxine stimulates filaggrin production in human epidermal keratinocytes
Molecular Biology Reports (2021)