Modulation of autoimmune diabetes by N-ethyl-N-nitrosoureainduced mutations in non-obese diabetic mice

Lucienne Chatenoud, Cindy Marquet, Fabrice Valette, Lindsay Scott, Jiexia Quan, Chun Hui Bu, Sara Hildebrand, Eva Marie Y. Moresco, Jean Francois Bach, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic association studies of type 1 diabetes (T1D) in humans, and in congenic non-obese diabetic (NOD) mice harboring DNA segments from T1D-resistant mice, face the challenge of assigning causation to specific gene variants among many within loci that affect disease risk. Here, we created random germline mutations in NOD/NckH mice and used automated meiotic mapping to identify mutations modifying T1D incidence and age of onset. In contrast with association studies in humans or congenic NOD mice, we analyzed a relatively small number of genetic changes in each pedigree, permitting implication of specific mutations as causative. Among 844 mice from 14 pedigrees bearing 594 coding/splicing changes, we identified seven mutations that accelerated T1D development, and five that delayed or suppressed T1D. Eleven mutations affected genes not previously known to influence T1D (Xpnpep1, Herc1, Srrm2, Rapgef1, Ppl, Zfp583, Aldh1l1, Col6a1, Ccdc13, Cd200r1, Atrnl1). A suppressor mutation in Coro1a validated the screen. Mutagenesis coupled with automated meiotic mapping can detect genes in which allelic variation influences T1D susceptibility in NOD mice. Variation of some of the orthologous/paralogous genes may influence T1D susceptibility in humans.

Original languageEnglish (US)
Article numberdmm049484
JournalDMM Disease Models and Mechanisms
Volume15
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • Autoimmune diabetes
  • Automated meiotic mapping
  • Genetics
  • Non-obese diabetic (NOD) mice
  • Protective locus
  • Risk locus
  • Type 1 diabetes

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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