A novel form of human STAT1 deficiency impairing early but not late responses to interferons
A novel form of human STAT1 deficiency impairing early but not late responses to interferons
复制标题
DOI：
10.1182/blood-2010-04-280586
复制
发表时间：
2010-12-23
期刊：
影响因子：
20.3
通讯作者：
Boisson-Dupuis, Stephanie
中科院分区：
文献类型：
--
作者：
Kong, Xiao-Fei;Ciancanelli, Michael;Boisson-Dupuis, Stephanie
常染色体隐性遗传性STAT1缺乏症与细胞对干扰素的反应受损以及对细胞内细菌和病毒感染的易感性有关。我们在这里报告了一种新的形式的部分STAT1缺乏症的两个兄弟姐妹呈现分枝杆菌和病毒疾病。两者都携带着STAT1基因第201(K201N)位用天冬酰胺残基取代赖氨酸的纯合错义突变。这种突变导致大多数STAT1 mRNA8外显子的异常剪接，从而降低(类似于70%)STAT1蛋白水平。突变的STAT1蛋白在酪氨酸磷酸化、去磷酸化、同源二聚为伽马激活因子和异源三聚为ISGF-3、与特定的DNA元件结合和转录激活方面没有本质上的有害。有趣的是，伽马激活因子和ISGF3的激活仅在患者的各种细胞中的早期时间点受到损害(在刺激的1小时内)，而持续的损害发生在其他已知形式的完全和部分隐性STAT1缺乏症中。因此，延迟反应是正常的；然而，干扰素刺激基因的早期诱导被选择性地严重损害。因此，细胞对人类干扰素的早期反应严重依赖于STAT1的量，对于适当控制分枝杆菌和病毒感染是必不可少的。(血。2010；116(26)：5895-5906)
Autosomal recessive STAT1 deficiency is associated with impaired cellular responses to interferons and susceptibility to intracellular bacterial and viral infections. We report here a new form of partial STAT1 deficiency in 2 siblings presenting mycobacterial and viral diseases. Both carried a homozygous missense mutation replacing a lysine with an asparagine residue at position 201 (K201N) of STAT1. This mutation causes the abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing (by similar to 70%) STAT1 protein levels. The mutant STAT1 proteins are not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into gamma-activating factor and heterotrimerization into ISGF-3, binding to specific DNA elements, and activation of the transcription. Interestingly, the activation of gamma-activating factor and ISGF3 was impaired only at early time points in the various cells from patient (within 1 hour of stimulation), whereas sustained impairment occurs in other known forms of complete and partial recessive STAT1 deficiency. Consequently, delayed responses were normal; however, the early induction of interferon-stimulated genes was selectively and severely impaired. Thus, the early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections. (Blood. 2010;116(26):5895-5906)