Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder.
Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder.
复制标题
钙释放激活通道调节因子2A（CRACR2A）的双等位基因突变导致原发性免疫缺陷疾病。
DOI：
10.7554/elife.72559
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发表时间：
2021-12-15
期刊：
影响因子：
7.7
通讯作者：
Savic S
中科院分区：
文献类型：
--
作者：
Wu B;Rice L;Shrimpton J;Lawless D;Walker K;Carter C;McKeown L;Anwar R;Doody GM;Srikanth S;Gwack Y;Savic S
CRAC通道调节因子2 A(CRACR2 A)是一种在T细胞中大量表达的大分子Rab GTP酶，在T细胞受体刺激和激活Ca~(2+)-NFAT和JNK-AP1通路之间起信号传递作用。在许多全基因组关联研究中，CRACR2A与人类疾病有关，然而，到目前为止，还没有发现CRACR2A具有破坏性变异的患者。在这项研究中，我们描述了一名患者在CRACR2A[父亲的等位基因c.834 Gag>；Gat(p.E278D)和母亲的等位基因c.430 Aga>；GGA(p.R144G)c.898 Gag>；tag(p.E300*)]中存在双等位基因变异。患者33岁，来自东亚，表现为迟发性的联合免疫缺陷，特征是反复的胸部感染，全丙种球蛋白血症和CD4+T细胞淋巴细胞减少。在体外，患者B细胞暴露在T依赖刺激下可产生正常的抗体分泌细胞，但患者T细胞CRACR2A蛋白水平显著降低，近端TCR信号减弱，包括SOCE抑制和JNK磷酸化减少，导致增殖和细胞因子产生缺陷。单个等位基因突变体在CRACR2A缺失的T细胞中的表达表明，CRACR2AE278D突变体不影响JNK的磷酸化，但损害SOCE，导致细胞因子产生减少。截短的双突变CRACR2AR144G/E300*显示出明显的JNK磷酸化缺陷和SOCE缺陷以及细胞因子产生的强烈障碍。因此，我们已经确定了CRACR2A的变异，这些变异导致了以T细胞功能丧失为特征的晚期联合免疫缺陷。
CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca2+-NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in CRACR2A [paternal allele c.834 gaG> gaT (p.E278D) and maternal alelle c.430 Aga > Gga (p.R144G) c.898 Gag> Tag (p.E300*)], the gene encoding CRACR2A. The 33-year-old patient of East-Asian origin exhibited late onset combined immunodeficiency characterised by recurrent chest infections, panhypogammaglobulinemia and CD4+ T cell lymphopenia. In vitro exposure of patient B cells to a T-dependent stimulus resulted in normal generation of antibody-secreting cells, however the patient’s T cells showed pronounced reduction in CRACR2A protein levels and reduced proximal TCR signaling, including dampened SOCE and reduced JNK phosphorylation, that contributed to a defect in proliferation and cytokine production. Expression of individual allelic mutants in CRACR2A-deleted T cells showed that the CRACR2AE278D mutant did not affect JNK phosphorylation, but impaired SOCE which resulted in reduced cytokine production. The truncated double mutant CRACR2AR144G/E300* showed a pronounced defect in JNK phosphorylation as well as SOCE and strong impairment in cytokine production. Thus, we have identified variants in CRACR2A that led to late-stage combined immunodeficiency characterized by loss of function in T cells.