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

Frances J D Smith¹, Alan D Irvine², Ana Terron-Kwiatkowski¹, Aileen Sandilands¹, Linda E Campbell¹, Yiwei Zhao¹, Haihui Liao¹, Alan T Evans³, David R Goudie⁴, Sue Lewis-Jones⁵, Gehan Arseculeratne⁵, Colin S Munro⁶, Ann Sergeant⁶, Gráinne O'Regan², Sherri J Bale⁷, John G Compton⁷, John J DiGiovanna^8, 9, Richard B Presland^10, 11, Philip Fleckman¹¹ & W H Irwin McLean¹

¹  Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

²  Department of Paediatric Dermatology, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.

³  Pathology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

⁴  Clinical Genetics, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

⁵  Dermatology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

⁶  Department of Dermatology, South Glasgow University Hospitals NHS Trust, Glasgow, G51 4TF, UK.

⁷  Gene Dx, Gaithersburg, Maryland 20877, USA.

⁸  Division of Dermatopharmacology, Department of Dermatology, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA.

⁹  Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

¹⁰  Oral Biology, School of Dentistry, University of Washington, Seattle, Washington 98195, USA.

¹¹  Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.

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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