title: Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.
abstract: Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.
authors.affiliation: Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Sandilands
authors.forename: Gráinne M
authors.initials: GM
authors.lastname: O'Regan
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ana
authors.initials: A
authors.lastname: Terron-Kwiatkowski
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Watson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cassidy
authors.forename: David R
authors.initials: DR
authors.lastname: Goudie
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Smith
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
mesh_terms: D003876:Dermatitis, Atopic / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D000091344:Filaggrin Proteins; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000453:epidemiology / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007494:Ireland / Q000453:epidemiology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D015995:Prevalence
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins