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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
W.H.I.M. and F.J.D.S. have filed patents relating to genetic testing and therapy development aimed at the filaggrin gene.
Filaggrin priming sites and FLG8+10+ allele. (PDF 579 kb)
PCR strategy and primers for exon 3. (PDF 128 kb)
Pedigrees and mutation data, additional immunohistochemistry and immunoblotting data and electron microscopy. (PDF 414 kb)
Filaggrin mutations and prevalence data. (PDF 82 kb)
SNP and microsatellite analysis. (PDF 77 kb)
Clinical details of atopic dermatitis case series. (PDF 86 kb)
Primers and probes for mutation screening. (PDF 93 kb)
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
Clinical and Experimental Dermatology (2020)
Annals of Allergy, Asthma & Immunology (2020)
Environmental Research (2019)
Frontiers in Immunology (2019)
Genetic variants of filaggrin are associated with occupational dermal exposure and blood DNA alterations in hairdressers
Science of The Total Environment (2019)