1. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects
- Author
-
Saunders, Sean P, Goh, Christabelle SM, Brown, Sara J, Palmer, Colin NA, Porter, Rebecca M, Cole, Christian, Campbell, Linda E, Gierlinski, Marek, Barton, Geoffrey J, Schneider, Georg, Balmain, Allan, Prescott, Alan R, Weidinger, Stephan, Baurecht, Hansjörg, Kabesch, Michael, Gieger, Christian, Lee, Young-Ae, Tavendale, Roger, Mukhopadhyay, Somnath, Turner, Stephen W, Madhok, Vishnu B, Sullivan, Frank M, Relton, Caroline, Burn, John, Meggitt, Simon, Smith, Catherine H, Allen, Michael A, Barker, Jonathan NWN, Reynolds, Nick J, Cordell, Heather J, Irvine, Alan D, McLean, WH Irwin, Sandilands, Aileen, and Fallon, Padraic G
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Genetics ,Eczema / Atopic Dermatitis ,Aetiology ,2.1 Biological and endogenous factors ,Skin ,Animals ,Dermatitis ,Atopic ,Filaggrin Proteins ,Gene Expression ,Genetic Predisposition to Disease ,Humans ,Male ,Membrane Proteins ,Mice ,Mutation ,Phenotype ,Physical Chromosome Mapping ,Polymorphism ,Single Nucleotide ,Allergy ,association ,atopic dermatitis ,atopy ,eczema ,filaggrin ,flaky tail ,Matt ,mattrin ,mouse ,mutation ,Tmem79 ,AD ,Atopic dermatitis ,DM ,Double mutant ,FLG ,Filaggrin ,HDM ,High-power field ,House dust mite ,MAPEG ,Membrane-associated proteins in eicosanoid and glutathione metabolism ,OR ,Odds ratio ,SNP ,Single nucleotide polymorphism ,TEWL ,Transepidermal water loss ,WT ,Wild-type ,hpf - 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. Matt(ft) 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, rs6684514, [corrected] 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.
- Published
- 2013