An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity
An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity
复制标题
DOI：
10.1016/s0092-8674(00)00209-9
复制
发表时间：
2000-12-22
期刊：
影响因子：
64.5
通讯作者：
Weiss, A
中科院分区：
文献类型：
--
作者：
Majeti, R;Xu, Z;Weiss, A
已经提出了一个模型，用于调节CD45，并通过同源性其他RPTP，其中二聚化通过抑制性结构楔和催化位点之间的对称相互作用抑制磷酸酶活性。在这里，我们报告的表型的小鼠与一个单一的点突变，谷氨酸613精氨酸，失活的抑制楔CD45。CD45 E613 R突变引起多克隆淋巴细胞活化，导致淋巴细胞增殖和严重的自身免疫性肾炎，产生自身抗体，导致死亡。纯合子和杂合子均发生病理学改变，表明CD45 E613 R的遗传优势。CD45 E613 R小鼠的显著表型证明了通过二聚化负调节CD45的体内重要性，支持了CD45和RPTP调节的一般模型。
A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site. Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45. The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death. Both homozygotes and heterozygotes develop pathology, indicating genetic dominance of CD45 E613R. The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general.