CRISPR-Cas9 mediated modification of the NOD mouse genome with Ptpn22R619W mutation increases autoimmune diabetes

An allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), PTPN22 R620W , is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by 2-4 fold. The non-obese diabetic (NOD) mouse is a spontaneous T1D model that shares with humans many genetic pathways contributing to T1D. We hypothesized that the introduction of the murine orthologous Ptpn22 R619W mutation to the NOD genome would enhance the spontaneous development of T1D. We micro-injected CRISPR-Cas9 and homology directed repair template into NOD single-cell zygotes to introduce the Ptpn22 R619W mutation to its endogenous locus. The resulting Ptpn22 R619W mice showed increased insulin auto-antibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22 R620W and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice.