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

Anne Perrine Foray, Sophie Candon, Sara Hildebrand, Cindy Marquet, Fabrice Valette, Coralie Pecquet, Sebastien Lemoine, Francina Langa-Vives, Michael Dumas, Peipei Hu, Pere Santamaria, Sylvaine You, Stephen Lyon, Lindsay Scott, Chun Hui Bu, Tao Wang, Darui Xu, Eva Marie Y. Moresco, Claudio Scazzocchio, Jean François BachBruce Beutler, Lucienne Chatenoud

Research output: Contribution to journalArticlepeer-review

Abstract

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. Wholegenome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of sublinespecific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH 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/NckL 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.

Original languageEnglish (US)
Article numbere2112032118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number47
DOIs
StatePublished - Nov 23 2021

Keywords

  • Autoimmunity
  • Genetic mapping
  • NOD mouse
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes'. Together they form a unique fingerprint.

Cite this