Abstract
BackgroundAtopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.ObjectiveWe sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.MethodsA mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD.ResultsThe matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD.ConclusionIn mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
Highlights
Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD
Previously, we demonstrated that filaggrin gene (FLG) loss-of-function mutations have a very strong relevance for the common inflammatory skin disease AD and associated atopic phenotypes[3,9,10] and identified an analogous mutation in the murine homolog Flg in the spontaneously occurring flaky tail DM mouse.[12]
These DM mice have been widely used as a model of heritable skin barrier deficiency and spontaneous dermatitis[13,14,15,17] and as a model of filaggrin deficiency–associated AD pathogenesis in patients.[29]
Summary
Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in. Supported by the Wellcome Trust (Programme grant 092530/Z/10/Z to W.H.I.M., A.D.I., G.J.B., and P.G.F.; Bioresources grant 090066/B/09/Z to A.D.I., W.H.I.M., and S.J.B.; Clinical Intermediate Fellowship WT086398MA to S.J.B.; and Senior Fellowship 087436 to H.J.C.); the Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics (to N.J.R.); Wellcome. Trust Bioresources grant 099177/Z/12/Z (to C.N.A.P.); the Medical Research Council (Programme grant G0802780 to W.H.I.M.); the Science Foundation Ireland The Centre for Dermatology and Genetic Medicine, University of Dundee, is supported by a Wellcome Trust
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