CRISPR-Cas9–Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes
| Autor: | Douglas R. Green, Christian J. Maine, Linda A. Sherman, Yang D. Dai, Xiaotian Lin, Stephanie Rigaud, Stephane Pelletier, Greg S. Martin, Liping Yu, Kristi Marquardt, Ling Jiang, Sebastien Gingras, Karsten Sauer, Sergey Kupriyanov, Alberto R. Rodriguez |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine endocrine system Genotype endocrine system diseases Endocrinology Diabetes and Metabolism Blotting Western Technological Advances Locus (genetics) Protein tyrosine phosphatase Nod Biology Polymorphism Single Nucleotide PTPN22 Mice 03 medical and health sciences Mice Inbred NOD immune system diseases Internal Medicine Animals Humans CRISPR Genetic Predisposition to Disease Allele Alleles NOD mice Mice Knockout Genetics Genome Reverse Transcriptase Polymerase Chain Reaction nutritional and metabolic diseases Protein Tyrosine Phosphatase Non-Receptor Type 22 Penetrance Diabetes Mellitus Type 1 030104 developmental biology Mutation Female CRISPR-Cas Systems |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22R620W, is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by two- to fourfold. The 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 Ptpn22R619W mutation to the NOD genome would enhance the spontaneous development of T1D. We microinjected CRISPR-Cas9 and a homology-directed repair template into NOD single-cell zygotes to introduce the Ptpn22R619W mutation to its endogenous locus. The resulting Ptpn22R619W mice showed increased insulin autoantibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22R620W and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice. |
| Databáze: | OpenAIRE |
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