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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Saunders, Sean P.^1,2,3  Goh, Christabelle S. M.⁴  Brown, Sara J.⁴  Palmer, Colin N. A.⁵  Porter, Rebecca M.^1,4  Cole, Christian^4,6  Campbell, Linda E.⁴  Gierlinski, Marek⁶  Barton, Geoffrey J.⁶  Schneider, Georg⁹  Balmain, Allan^7,10  Weidinger, Stephan¹¹  Baurecht, Hansjoerg¹¹  Kabesch, Michael¹²  Gieger, Christian¹³  Lee, Young-Ae^14,15  Tavendale, Roger⁵  Mukhopadhyay, Somnath¹⁶  Turner, Stephen W.¹⁷  Madhok, Vishnu B.^8,18  Sullivan, Frank M.^8,18  Meggitt, Simon¹⁹  Smith, Catherine H.²⁰  Allen, Michael A.²⁰  Barker, Jonathan N. W. N.²⁰  Reynolds, Nick J.²¹  Irvine, Alan D.^1,2,22  McLean, W. H. Irwin⁴  Sandilands, Aileen⁴  Fallon, Padraic G.^1,2,3 

[1] Univ Dublin Trinity Coll, Sch Med, Dublin 2, Ireland

[2] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin, Ireland

[3] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Dublin 2, Ireland

[4] Univ Dundee, Ctr Dermatol & Genet Med, Dundee DD1 4HN, Scotland

[5] Univ Dundee, Biomed Res Inst, Dundee DD1 4HN, Scotland

[6] Univ Dundee, Bioinformat Res Grp, Dundee DD1 4HN, Scotland

[7] Univ Dundee, Div Cell Signalling & Immunol, Dundee DD1 4HN, Scotland

[8] Univ Dundee, Dundee DD1 4HN, Scotland

[9] ASTAR, Bioinformat Inst, Singapore, Singapore

[10] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[11] Univ Hosp Schleswig Holstein, Dept Dermatol Allergy & Venerol, Kiel, Germany

[12] Childrens Hosp Regensburg, Dept Pediat Pneumol & Allergy, Regensburg, Germany

[13] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[14] Charite, D-13353 Berlin, Germany

[15] Max Delbruck Ctr Mol Med MDC, Berlin, Germany

[16] Royal Alexandra Childrens Hosp, Brighton & Sussex Med Sch, Acad Dept Paediat, Brighton, E Sussex, England

[17] Univ Aberdeen, Dept Child Hlth, Aberdeen AB9 1FX, Scotland

[18] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[19] Royal Victoria Infirm, Dept Dermatol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[20] Kings Coll London, St Johns Inst Dermatol, London WC2R 2LS, England

[21] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[22] Our Ladys Childrens Hosp, Dept Paediat Dermatol, Dublin, Ireland

关键词: Allergy;    association;    atopic dermatitis;    atopy;    eczema;    filaggrin;    flaky tail;    Matt;    mattrin;    mouse;    mutation;    Tmem79;   

DOI  :  10.1016/j.jaci.2013.08.046

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free