A SNP in the Immunoregulatory Molecule CTLA-4 Controls mRNA Splicing In Vivo but Does Not Alter Diabetes Susceptibility in the NOD Mouse
A SNP in the Immunoregulatory Molecule CTLA-4 Controls mRNA Splicing In Vivo but Does Not Alter Diabetes Susceptibility in the NOD Mouse
复制标题
免疫调节分子 CTLA-4 中的 SNP 控制体内 mRNA 剪接，但不会改变 NOD 小鼠的糖尿病易感性
作者：
Fabian Jakubczik;K. Jones;J. Nichols;William Mansfield;A. Cooke;N. Holmes
CTLA-4是自身免疫中的关键“检查点”调节剂。在人类和NOD小鼠研究中，CTLA-4同种型表达的变化与1型糖尿病的发展有关。在NOD小鼠中，次要亚型配体非依赖性CTLA-4的表达增加与糖尿病减少之间的因果关系已被广泛接受。CTLA-4的剪接改变归因于Ctla 4外显子2（e2_77A/G）中的单核苷酸多态性（SNP）。为了研究这种联系，我们使用NOD胚胎干细胞（ES）产生一种新的NOD转基因系与77 A/G SNP。该品系表型模仿了在B10 Idd 5.1小鼠中观察到的朝向liCTLA 4同种型的剪接增加。至关重要的是，SNP不会改变糖尿病的自发发病率、环磷酰胺诱导的糖尿病的发病率或过继转移后致糖尿病T细胞受体转基因CD 4 + T细胞的活化。我们的研究结果表明，B10和NOD基因组之间的许多其他连锁遗传变异中的一个或多个是Idd5.1赋予的糖尿病保护所必需的。由于NOD小鼠模型非常接近人类疾病，我们的数据表明，NOD背景下的基因敲入转基因小鼠可以检测与人类糖尿病相关的致病突变。
CTLA-4 is a critical “checkpoint” regulator in autoimmunity. Variation in CTLA-4 isoform expression has been linked to type 1 diabetes development in human and NOD mouse studies. In the NOD mouse, a causative link between increased expression of the minor isoform ligand-independent CTLA-4 and a reduction in diabetes has become widely accepted. Altered splicing of CTLA-4 has been attributed to a single nucleotide polymorphism (SNP) in Ctla4 exon2 (e2_77A/G). To investigate this link, we have used NOD embryonic stem (ES) cells to generate a novel NOD transgenic line with the 77A/G SNP. This strain phenocopies the increase in splicing toward the liCTLA4 isoform seen in B10 Idd5.1 mice. Crucially, the SNP does not alter the spontaneous incidence of diabetes, the incidence of cyclophosphamide-induced diabetes, or the activation of diabetogenic T-cell receptor transgenic CD4+ T cells after adoptive transfer. Our results show that one or more of the many other linked genetic variants between the B10 and NOD genome are required for the diabetes protection conferred by Idd5.1. With the NOD mouse model closely mimicking the human disease, our data demonstrate that knock-in transgenic mice on the NOD background can test causative mutations relevant in human diabetes.
影响因子：
32.4
作者：
Vijayakrishnan, L;Slavik, JM;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
56.9
作者：
HASKINS, K;MCDUFFIE, M
通讯作者：
MCDUFFIE, M