CRISPR-Cas9-Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes.
CRISPR-Cas9-Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes.
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DOI：
10.2337/db16-0061
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发表时间：
2016-08
期刊：
影响因子：
7.7
通讯作者：
Sherman LA
中科院分区：
文献类型：
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作者：
Lin X;Pelletier S;Gingras S;Rigaud S;Maine CJ;Marquardt K;Dai YD;Sauer K;Rodriguez AR;Martin G;Kupriyanov S;Jiang L;Yu L;Green DR;Sherman LA
蛋白酪氨酸磷酸酶非受体22（PTPN 22）的等位基因变体PTPN 22 R620 W与人类1型糖尿病（T1 D）密切相关，并使T1 D的风险增加2至4倍。NOD小鼠是一种自发的T1 D模型，与人类共享许多导致T1 D的遗传途径。我们假设，在NOD基因组中引入小鼠正向Ptpn 22 R619 W突变将增强T1 D的自发发展。我们将CRISPR-Cas9和同源定向修复模板显微注射到NOD单细胞合子中，以将Ptpn 22 R619 W突变引入其内源性基因座。得到的Ptpn 22 R619 W小鼠显示出增加的胰岛素自身抗体和更早的T1 D发作和更高的T1 D发病率。这是第一份证明小鼠模型人PTPN 22 R620 W中增强的T1 D以及CRISPR-Cas9用于NOD小鼠的直接遗传改变的效用的报告。
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.