type 1 diabetes (mouse) (PRJCA019096)

ALR/Lt is a congenic strain for autoimmune diabetes-prone NOD/ShiLtJ mice. They share 85% genomic identity, but ALR mice do not develop autoimmune diabetes, indicating that the unique 15% ALR genome encodes protective loci against autoimmune diabetes. Herein, we demonstrated that dendritic cells (DCs) originated from ALR mice have impaired migratory and T cell priming capability. Genomic comparative analysis characterized a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene on chromosome 8 as compared to that of NOD genome. An ALR Myo9b knock-in (KI) model and a DC specific Myo9b knockout (KO) model were then generated, and studies in these mice revealed that ALR Myo9b KI prevented the development and progression of spontaneous autoimmune diabetes in NOD mice, at an intermediate level between WT and DC specific Myo9b KO mice, suggesting that ALR Myo9b causes a loss-of-function phenotype. We conducted targeted sequencing of MYO9B along with comparative biostatistical analysis in 260 T1D cases and 240 healthy controls. A MYO9B R133Q polymorphism was identified in T1D patients, which is highly associated with an increased T1D risk coupled with enhanced DC function.