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

Lookup NU author(s): Dr Sara Brown, Dr Stephen Turner, Professor Caroline Relton, Professor Sir John BurnORCiD, Dr Simon Meggitt, Professor Nick ReynoldsORCiD, Professor Heather Cordell

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Abstract

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.


Publication metadata

Author(s): Saunders SP, Goh CSM, Brown SJ, Palmer CNA, Porter RM, Cole C, Campbell LE, Gierlinski M, Barton GJ, Schneider G, Balmain A, Prescott AR, Weidinger S, Baurecht H, Kabesch M, Gieger C, Lee YA, Tavendale R, Mukhopadhyay S, Turner SW, Madhok VB, Sullivan FM, Relton C, Burn J, Meggitt S, Smith CH, Allen MA, Barker JNWN, Reynolds NJ, Cordell HJ, Irvine AD, McLean WHI, Sandilands A, Fallon PG

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2013

Volume: 132

Issue: 5

Pages: 1121-1129

Print publication date: 01/11/2013

Online publication date: 29/09/2013

Acceptance date: 16/08/2013

Date deposited: 15/04/2015

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Mosby, Inc.

URL: http://dx.doi.org/10.1016/j.jaci.2013.08.046

DOI: 10.1016/j.jaci.2013.08.046


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Funding

Funder referenceFunder name
Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics
National Children's Research Centre
087436Wellcome Trust
090066/B/09/ZWellcome Trust
098439/Z/12/ZWellcome Trust
092530/Z/10/ZWellcome Trust
099177/Z/12/ZWellcome Trust
CZB/4/285Scottish Executive Health Department
G0802780Medical Research Council
NCI U01 CA141455National Cancer Institute
WT086398MAWellcome Trust

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