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首页> 外文期刊>The journal of clinical investigation >A human immunodeficiency caused by mutations in the PIK3R1gene
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A human immunodeficiency caused by mutations in the PIK3R1gene

机译：由PIK3R1基因突变引起的人类免疫缺陷

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Recently, patient mutations that activate PI3K signaling have been linked to a primaryantibody deficiency. Here, we used whole-exome sequencing and characterized the moleculardefects in 4 patients from 3 unrelated families diagnosed with hypogammaglobulinemia andrecurrent infections. We identified 2 different heterozygous splice site mutations thataffect the same splice site in PIK3R1 , which encodes the p85αsubunit of PI3K. The resulting deletion of exon 10 produced a shortened p85α proteinthat lacks part of the PI3K p110-binding domain. The hypothetical loss ofp85α-mediated inhibition of p110 activity was supported by elevated phosphorylationof the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patientblood revealed that naive T and memory B cell counts were low, and T cell blasts displayedenhanced activation-induced cell death, which was corrected by addition of the PI3Kδinhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response toactivation via the B cell receptor and TLR9, indicating a B cell defect. The phenotypeexhibited by patients carrying the PIK3R1 splice site mutation is similarto that of patients carrying gain-of-function mutations in PIK3CD . Ourresults suggest that PI3K activity is tightly regulated in T and B lymphocytes and thatvarious defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
机译：最近，激活PI3K信号的患者突变已与原发性抗体缺乏症相关。在这里，我们使用全外显子组测序，并鉴定了来自3个无关家族的4名患者的分子缺陷，这些患者被诊断为低球蛋白血症和反复感染。我们确定了2个不同的杂合剪接位点突变，它们影响PIK3R1中的相同剪接位点，该位点编码PI3K的p85α亚基。所得外显子10的缺失产生了缩短的p85α蛋白，该蛋白缺少PI3K p110结合结构域的一部分。 p85α介导的对p110活性抑制的假设性丧失是由患者T细胞母细胞中已知的下游信号激酶AKT磷酸化水平升高所支持的。对患者血液的分析表明，幼稚的T细胞和记忆B细胞计数较低，T细胞胚细胞显示出增强的激活诱导的细胞死亡，这可以通过添加PI3Kδ抑制剂IC87114加以纠正。此外，响应于经由B细胞受体和TLR9的活化，B淋巴细胞增殖较弱，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的功能获得性突变的患者表现出的表型相似。我们的结果表明PI3K活性在T和B淋巴细胞中受到严格调节，并且PI3K触发的途径中的各种缺陷均可引起原发性免疫缺陷。

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