Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 5; pp. 1121 - 1129
• Main Authors: Saunders, Sean P., PhD, Goh, Christabelle S.M., BSc, Brown, Sara J., MD, Palmer, Colin N.A., PhD, Porter, Rebecca M., PhD, Cole, Christian, PhD, Campbell, Linda E., MSc, Gierlinski, Marek, PhD, Barton, Geoffrey J., PhD, Schneider, Georg, PhD, Balmain, Allan, PhD, Prescott, Alan R., PhD, Weidinger, Stephan, MD, PhD, Baurecht, Hansjörg, PhD, Kabesch, Michael, MD, Gieger, Christian, PhD, Lee, Young-Ae, MD, Tavendale, Roger, PhD, Mukhopadhyay, Somnath, MD, Turner, Stephen W., MD, Madhok, Vishnu B., MD, Sullivan, Frank M., MD, Relton, Caroline, PhD, Burn, John, MD, Meggitt, Simon, MD, Smith, Catherine H., MD, Allen, Michael A., PhD, Barker, Jonathan N.W. N., MD, Reynolds, Nick J., MD, Cordell, Heather J., DPhil, Irvine, Alan D., MD, McLean, W.H. Irwin, DSc, Sandilands, Aileen, PhD, Fallon, Padraic G., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-11-2013; Elsevier; Elsevier Limited; Mosby
• Subjects: Allergic diseases; Allergy; Allergy and Immunology; Animals; association; Asthma; atopic dermatitis; Atopic Dermatitis and Skin Disease; atopy; Bioinformatics; Biological and medical sciences; Deoxyribonucleic acid; Dermatitis, Atopic - genetics; Dermatitis, Atopic - immunology; Dermatitis, Atopic - pathology; DNA; eczema; filaggrin; Filaggrin Proteins; flaky tail; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Genes; Genetic Predisposition to Disease; Genomes; Humans; Immunopathology; Male; Matt; mattrin; Medical sciences; Membrane Proteins - genetics; Mice; mouse; Mutation; Pediatrics; Phenotype; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Population; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin - metabolism; Skin - pathology; Skin allergic diseases. Stinging insect allergies; Studies; Tmem79; FLG; Allergy; MAPEG; association; atopic dermatitis; DM; Matt; HDM; mouse; SNP; eczema; filaggrin; WT; hpf; TEWL; AD; OR; flaky tail; mattrin; Tmem79; High-power field; atopy; House dust mite; Transepidermal water loss; Wild-type; mutation; Double mutant; Odds ratio; Single nucleotide polymorphism; Membrane-associated proteins in eicosanoid and glutathione metabolism; Human; Immunopathology; Skin disease; Rodentia; Filaggrin; Atopy; Vertebrata; Mammalia; Association; Immunology; Gene; Mouse; Atopic dermatitis; Animal; Eczema; Predisposition; Genetics; Mutation
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.08.046

Background 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 Flg and also carry an unknown gene, matted , causing a matted hair phenotype. Objective We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. Methods A 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. Results The 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, rs6694514, in the human MATT gene has a small but significant association with AD. Conclusion In 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.