Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects - 30/10/13
Doi : 10.1016/j.jaci.2013.08.046
Sean P. Saunders, PhD a, b, c, ∗, Christabelle S.M. Goh, BSc d, ∗, Sara J. Brown, MD d, Colin N.A. Palmer, PhD e, Rebecca M. Porter, PhD a, d, Christian Cole, PhD d, f, Linda E. Campbell, MSc d, Marek Gierlinski, PhD f, Geoffrey J. Barton, PhD f, Georg Schneider, PhD g, Allan Balmain, PhD h, Alan R. Prescott, PhD i, Stephan Weidinger, MD, PhD j, Hansjörg Baurecht, PhD j, Michael Kabesch, MD k, Christian Gieger, PhD l, Young-Ae Lee, MD m, Roger Tavendale, PhD e, Somnath Mukhopadhyay, MD n, Stephen W. Turner, MD o, Vishnu B. Madhok, MD p, Frank M. Sullivan, MD p, Caroline Relton, PhD q, John Burn, MD q, Simon Meggitt, MD r, Catherine H. Smith, MD s, Michael A. Allen, PhD s, Jonathan N.W. N. Barker, MD s, Nick J. Reynolds, MD t, Heather J. Cordell, DPhil q, Alan D. Irvine, MD a, b, u, W.H. Irwin McLean, DSc d, ⁎ 
, Aileen Sandilands, PhD d, Padraic G. Fallon, PhD a, b, c, ⁎
, Aileen Sandilands, PhD d, Padraic G. Fallon, PhD a, b, c, ⁎ a School of Medicine, Trinity College Dublin, Dublin, Ireland
b National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland
c Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
d Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom
e Biomedical Research Institute, University of Dundee, Dundee, United Kingdom
f Bioinformatics Research Group, University of Dundee, Dundee, United Kingdom
i Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
p Population Health Sciences, University of Dundee, Dundee, United Kingdom
g Bioinformatics Institute, A*STAR, Singapore
h Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, Calif
j Department of Dermatology, Allergy, and Venerology, University Hospital Schleswig-Holstein, Kiel, Germany
k Department of Pediatric Pneumology and Allergy, Children's Hospital Regensburg, Regensburg, Germany
l Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
m Pediatric Pneumology and Immunology, Charité University Medicine Berlin and Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Berlin, Germany
n Academic Department of Paediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, United Kingdom
o Department of Child Health, University of Aberdeen, Aberdeen, United Kingdom
q Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
r Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
s St John's Institute of Dermatology, King's College London, London, United Kingdom
t Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom
u Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
∗Corresponding author: Padraic G. Fallon, PhD, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.∗W. H. Irwin McLean, DSc, Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
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. 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.
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.
El texto completo de este artículo está disponible en PDF.Key words : Allergy, association, atopic dermatitis, atopy, eczema, filaggrin, flaky tail, Matt, mattrin, mouse, mutation, Tmem79
Abbreviations used : AD, DM, FLG, HDM, hpf, MAPEG, OR, SNP, TEWL, WT
Esquema
| 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 (to P.G.F.); the National Children's Research Centre (to P.G.F. and A.D.I.); and the National Cancer Institute (NCI U01 CA141455 to A.B.). The Centre for Dermatology and Genetic Medicine, University of Dundee, is supported by a Wellcome Trust Strategic Award (098439/Z/12/Z to W.H.I.M. and G.J.B.). The PAGES, BREATHE, and GS:3D cohorts were funded by the Scottish Executive Health Department (CZB/4/285). |
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| Disclosure of potential conflict of interest: S. P. Saunders has been supported by one or more grants from the Wellcome Trust. S. J. Brown has been supported by one or more grants from the Wellcome Trust, National Children's Research Centre Dublin (Ireland), and Anonymous Trustees, Dundee, United Kingdom; is employed by NHS Tayside; and has received one or more payments for lecturing from or is on the speakers' bureau for the American Academy of Allergy, Asthma & Immunology. C. Cole has been supported by one or more grants from the Wellcome Trust. G. J. Barton has been supported by one or more grants from the Wellcome Trust. A. Balmain has been supported by one or more grants from the National Cancer Institute. S. Weidinger has been supported by one or more grants from the National Genome Research Network. M. Kabesch has been supported by one or more grants from the European Union, the German Ministry of Education and Research, and the German Research Foundation and has received one or more payments for lecturing from or is on the speakers' bureau for ERS, EIAACI, ATS, Novartis, and GlaxoSmithKline. Y.-A. Lee has been supported by one or more grants from the German Ministry of Education and Research and from the German Research Foundation. S. Mukhopadhyay has been supported by one or more grants from Scottish Enterprises, the Perth and Kinross Council, the Gannochy Trust, and the Translational Medical Research Consortium; has received one or more consulting fees or honoraria from the Translational Medicine Research Consortium; is employed by Brighton and Sussex Medical School; has provided expert testimony for the Central Legal Office, Scotland; has received one or more grants from or has one or more grants pending with the National Institute of Health Research; has one or more patents planned, pending, or issued unrelated to this article; and has received one or more payments for the development of educational presentations for Thermo Fisher. F. M. Sullivan has been supported by one or more grants from the Chief Scientist Office Scotland. J. Burn is the Medical Director for Quantum Dx Ltd. H. J. Cordell is a Board member for Wiley-Blackwell Life Science Journals; is employed by Newcastle University; has received one or more grants from or has one or more grants pending with the Wellcome Trust, the Medical Research Council, and NIAAA; and has received one or more payments for lecturing from or is on the speakers' bureau for Erasmus University Rotterdam, the Wellcome Trust, Rockefeller University, and the Ontario Institute for Cancer Research. N. J. Reynolds has been supported by a Wellcome Trust Research Leave Award for Clinical Academics. A. D. Irvine has been supported by one or more grants from the Wellcome Trust. P. G. Fallon has been supported by one or more grants from Science Foundation Ireland, the National Children's Research Centre, and the Wellcome Trust. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2013
The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
Vol 132 - N° 5
P. 1121-1129 - novembre 2013 Regresar al número
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Bienvenido a EM-consulte, la referencia de los profesionales de la salud.
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