Feske Stefan, Gwack Yousang, Prakriya Murali, Srikanth Sonal, Puppel Sven-Holger, Tanasa Bogdan, Hogan Patrick G, Lewis Richard S, Daly Mark, Rao Anjana
The CBR Institute for Biomedical Research, and the Department of Pediatrics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature. 2006 May 11;441(7090):179-85. doi: 10.1038/nature04702. Epub 2006 Apr 2.
Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.
免疫细胞的抗原刺激会通过钙释放激活钙（CRAC）通道触发钙离子内流，通过激活转录因子NFAT促进对病原体的免疫反应。我们之前已经表明，患有一种遗传性严重联合免疫缺陷（SCID）综合征的患者的细胞在储存性钙离子内流和CRAC通道功能方面存在缺陷。在此，我们使用两种无偏差全基因组方法相结合来确定这些患者的基因缺陷：一种是使用单核苷酸多态性阵列的改良连锁分析，另一种是旨在识别储存性钙离子内流和NFAT核转运调节因子的果蝇RNA干扰筛选。两种方法都聚焦于一种我们称为Orai1的新蛋白，它含有四个假定的跨膜片段。这些SCID患者在ORAI1中存在一个单一错义突变的纯合子，并且在SCID T细胞中表达野生型Orai1可恢复储存性钙离子内流和CRAC电流（I(CRAC)）。我们提出Orai1是CRAC通道复合物的一个重要组成部分或调节因子。
