title: Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.
abstract: We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. 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 (chi2 test: P = 2.12 x 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.
authors.affiliation: Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Sandilands
authors.forename: Ana
authors.initials: A
authors.lastname: Terron-Kwiatkowski
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hull
authors.forename: Gráinne M
authors.initials: GM
authors.lastname: O'Regan
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Clayton
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Watson
authors.forename: Thomas
authors.initials: T
authors.lastname: Carrick
authors.forename: Alan T
authors.initials: AT
authors.lastname: Evans
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Linda E
authors.initials: LE
authors.lastname: Campbell
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Ivo
authors.initials: I
authors.lastname: Nagtzaam
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bradley
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
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: D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D000091344:Filaggrin Proteins; D016368:Frameshift Mutation / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism; D007494:Ireland; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D018389:Codon, Nonsense; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins