A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function
A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function
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DOI：
10.1038/nature04702
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发表时间：
2006-05-11
期刊：
影响因子：
64.8
通讯作者：
Rao, A
中科院分区：
文献类型：
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作者：
Feske, S;Gwack, Y;Rao, A
抗原刺激免疫细胞触发Ca（2+）通过Ca（2+）释放激活Ca(2+) （CRAC）通道进入，通过激活转录因子NFAT促进对病原体的免疫应答。我们之前已经证明，来自一种遗传性严重联合免疫缺陷（SCID）综合征患者的细胞在储存操作的Ca（2+）进入和CRAC通道功能方面存在缺陷。在这里，我们确定了这些患者的遗传缺陷，使用两种无偏倚的全基因组方法的组合：单核苷酸多态性阵列的改良连锁分析和果蝇RNA干扰筛选，旨在识别储存操作的Ca（2+）进入和NFAT核输入的调节因子。这两种方法都集中在一种新的蛋白质上，我们称之为Orai1，它包含四个假定的跨膜片段。SCID患者的ORAI1是纯合的，只有一个错义突变，野生型ORAI1在SCID T细胞中的表达恢复了储存操作的Ca（2+）内流和CRAC电流（I CRAC）。我们认为Orai1是CRAC通道复合体的重要组成部分或调节器。
Antigen stimulation of immune cells triggers Ca(2+) entry through Ca(2+) release-activated Ca(2+) ( 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) influx and the CRAC current ( I CRAC). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.