title: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
abstract: 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 schoolchildren. 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 approximately 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.
authors.affiliation: Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Smith
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.forename: Ana
authors.initials: A
authors.lastname: Terron-Kwiatkowski
authors.forename: Aileen
authors.initials: A
authors.lastname: Sandilands
authors.forename: Linda E
authors.initials: LE
authors.lastname: Campbell
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Alan T
authors.initials: AT
authors.lastname: Evans
authors.forename: David R
authors.initials: DR
authors.lastname: Goudie
authors.forename: Sue
authors.initials: S
authors.lastname: Lewis-Jones
authors.forename: Gehan
authors.initials: G
authors.lastname: Arseculeratne
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: Ann
authors.initials: A
authors.lastname: Sergeant
authors.forename: Gráinne
authors.initials: G
authors.lastname: O'Regan
authors.forename: Sherri J
authors.initials: SJ
authors.lastname: Bale
authors.forename: John G
authors.initials: JG
authors.lastname: Compton
authors.forename: John J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: Richard B
authors.initials: RB
authors.lastname: Presland
authors.forename: Philip
authors.initials: P
authors.lastname: Fleckman
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
mesh_terms: D002648:Child; D005260:Female; D000091344:Filaggrin Proteins; D006580:Genetic Carrier Screening; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics; D012016:Reference Values; D017384:Sequence Deletion
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010750:Phosphoproteins