De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes.

Autor:	Foray AP; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Candon S; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Hildebrand S; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Marquet C; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Valette F; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Pecquet C; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Lemoine S; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Langa-Vives F; Mouse Genetics Engineering Center, Institut Pasteur, 75724 Paris, France., Dumas M; CNRS UMR7242, Biotechnology and Cell Signaling, University of Strasbourg, 67412 Illkirch Cedex, France., Hu P; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Santamaria P; Julia McFarlane Diabetes Research Centre, Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada.; Consolidated Group of the Generalitat, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain., You S; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Lyon S; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Scott L; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Bu CH; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Wang T; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390., Xu D; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Moresco EMY; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Scazzocchio C; Section of Microbiology, Department of Infectious Diseases, Imperial College London, London SW7 2AZ, United Kingdom.; Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France., Bach JF; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France; jean-francois.bach@academie-sciences.fr Bruce.Beutler@UTSouthwestern.edu lucienne.chatenoud@inserm.fr.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France., Beutler B; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; jean-francois.bach@academie-sciences.fr Bruce.Beutler@UTSouthwestern.edu lucienne.chatenoud@inserm.fr., Chatenoud L; Institut Necker-Enfants Malades, Université de Paris, 75015 Paris, France; jean-francois.bach@academie-sciences.fr Bruce.Beutler@UTSouthwestern.edu lucienne.chatenoud@inserm.fr.; Institut Necker-Enfants Malades, CNRS UMR8253, Inserm UMR1151, 75015 Paris, France.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Nov 23; Vol. 118 (47).
DOI:	10.1073/pnas.2112032118
Abstrakt:	Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/Nck H and NOD/Nck L ) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/Nck H mice was unambiguously attributed to a recessive missense mutation of Dusp10 , which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/Nck L mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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