A human immunodeficiency caused by mutations in the PIK3R1 gene
A human immunodeficiency caused by mutations in the PIK3R1 gene
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DOI：
10.1172/jci75746
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Kracker, Sven
中科院分区：
文献类型：
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作者：
Deau, Marie-Celine;Heurtier, Lucie;Kracker, Sven
最近，激活PI3K信号的患者突变与一抗缺乏有关。在这里，我们使用全外显子组测序并表征了来自3个不相关家庭的4例低碳球蛋白血症和复发性感染患者的分子缺陷。我们发现了两个不同的杂合剪接位点突变，它们影响PIK3R1的同一剪接位点，PIK3R1编码PI3K的p85 α亚基。结果外显子10的缺失产生了缩短的p85 α蛋白，缺乏部分pi3k110结合域。p85 α介导的p110活性抑制的假设缺失得到了患者T细胞母细胞中已知下游信号激酶AKT磷酸化升高的支持。对患者血液的分析显示，初始T细胞和记忆B细胞计数较低，T细胞母细胞表现出增强的激活诱导的细胞死亡，这通过添加PI3K δ抑制剂IC87114来纠正。此外，B淋巴细胞对B细胞受体和TLR9的激活反应增殖弱，表明B细胞缺陷。携带PIK3R1剪接位点突变的患者表现出的表型与携带PIK3CD功能获得突变的患者相似。我们的研究结果表明，PI3K活性在T淋巴细胞和B淋巴细胞中受到严格调控，PI3K触发通路中的各种缺陷可导致原发性免疫缺陷。
Recently, patient mutations that activate PI3K signaling have beer linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogarnmaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85 alpha subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85 alpha protein that lacks part of the PI3K110-binding domain. The hypothetical loss of p85 alpha-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3K delta inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.