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Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris


Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren1. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

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Figure 1: Clinical appearance of ichthyosis vulgaris.
Figure 2: Pedigrees of ichthyosis vulgaris families studied.
Figure 3: FLG mutation detection and confirmation.
Figure 4: Morphological features of filaggrin-null ichthyosis vulgaris.

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This paper is dedicated to the memory of the late P.M. Steinert, who named filaggrin. Thanks to the patients and their families for their participation which made this research possible and to K. Johnston for clinical assistance. Thanks to 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 DNA sequencing and genotyping support; A. Grant and G. Milne, Pathology Department, for pathology support; and J. Mcfarlane, Epithelial Genetics Group, for clerical assistance. Thanks to M. Greenway, National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland for providing Irish control samples. This work was supported by a Wellcome Trust Senior Research Fellowship (W.H.I.M.), US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R.B.P.), and the Odland Endowed Research Fund (P.F., R.B.P.), as well as grants from The Dystrophic Epidermolysis Bullosa Research Association (W.H.I.M.), The Pachyonychia Congenita Project (F.J.D.S.) and The British Skin Foundation (F.J.D.S., W.H.I.M.).

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Correspondence to W H Irwin McLean.

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Supplementary information

Supplementary Fig. 1

Loss of filaggrin expression in cultured keratinocytes from an R501X homozygote. (PDF 2440 kb)

Supplementary Fig. 2

Biochemical evidence for loss of filaggrin production in the skin of an R501X homozygote. (PDF 2006 kb)

Supplementary Table 1

PCR primer sequences used for human filaggrin analysis. (PDF 16 kb)

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

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