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

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/Nck(H) and NOD/Nck(L)) 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/Nck(H) mice was unambiguously attributed to a recessive missense mutation of Dusp70, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp70 with CRISPR-Cas9 in NOD/Nck(L) mice, a manipulation that significantly increased disease incidence. The Dusp70 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against auto immune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

Automated summary

Insulin-dependent or type 1 diabetes (T1D) is a complex polygenic autoimmune disease with contributions from both common and rare genetic variants. Using NOD mice, researchers identified a recessive missense mutation in the Dusp70 gene that significantly increased disease incidence, highlighting the role of rare variants in altering disease phenotype. This study also revealed new insights into the genetic factors affecting T1D susceptibility and provided a potential target for therapeutic intervention.