De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice

Foray, A.-P.; Candon, S.; Hildebrand, S.; Marquet, C.; Valette, F.; Pecquet, C.; Lemoine, S.; Langa-Vives, F.; Dumas, M.; Hu, P.; Santamaria, P.; Lyon, S.; Scott, L.; Bu, C. H.; Wang, T.; Xu, D.; Moresco, E. M. Y.; Scazzocchio, C.; Bach, J.-F.; Beutler, B.; Chatenoud, L.

doi:10.1101/2020.12.30.424747

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bioRxiv · 10.1101/2020.12.30.424747

De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice

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Abstract

Here we report the isolation by selective breeding of two sublines of Non-Obese Diabetic (NOD) mice exhibiting a significant difference in the incidence of autoimmune type 1 diabetes (T1D). Whole genome sequencing of the NOD/NckH (high T1D incidence) and NOD/NckL (low T1D incidence) revealed the presence of a limited number of variants specific to each subline. Treating the age of T1D onset as a quantitative trait and using automated meiotic mapping (AMM), enhanced susceptibility in the NOD/NckH subline was unambiguously attributed to a recessive allele of Dusp10 which encodes a dual specificity phosphatase. The causative effect of the mutation was verified with a high level of confidence by targeting Dusp10 with CRISPR/Cas9 in NOD/NckL mice: in these animals a higher incidence of diabetes was observed. Expression of wild-type Dusp10 correlated with higher levels of surface PD-L1 in the islets of NOD/NckL mice.

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Foray, A.-P., Candon, S., Hildebrand, S., Marquet, C., Valette, F., Pecquet, C., Lemoine, S., Langa-Vives, F., Dumas, M., Hu, P., Santamaria, P., Lyon, S., Scott, L., Bu, C. H., Wang, T., Xu, D., Moresco, E. M. Y., Scazzocchio, C., Bach, J.-F., Beutler, B., Chatenoud, L.. 2021-01-04. De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice. https://doi.org/10.1101/2020.12.30.424747

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