Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema


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.

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Figure 1: Filaggrin variants and their biochemical consequences.

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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

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.

Correspondence to W H Irwin McLean or Alan D Irvine.

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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)

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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).

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