A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency
A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency
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DOI：
10.1016/j.ajhg.2012.08.006
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发表时间：
2012-10-05
影响因子：
9.8
通讯作者：
Aksentijevich, Ivona
中科院分区：
文献类型：
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作者：
Zhou, Qing;Lee, Geun-Shik;Aksentijevich, Ivona
在一个显性遗传性炎症性疾病家族中进行全外显子组测序，该家族的特征为复发性水疱性皮肤病变、细支气管炎、关节痛、眼部炎症、小肠结肠炎、缺乏自身抗体和轻度免疫缺陷。过滤来自三个样品的外显子组数据，包括受影响的父亲和女儿以及未受影响的母亲，以排除报告的变体，沿着良性变体，如通过PolyPhen-2确定的。总共有8个转录本被确定为可能的候选基因。我们确认了PLCG 2中的一个变异体c.2120C>A（p.Ser707Tyr）是唯一的新生变异体，存在于两个受影响的家族成员中，而不存在于四个未受影响的成员中。PLCG 2编码磷脂酶C γ 2（PLC γ 2），一种在各种免疫和炎症途径中具有关键调节作用的酶。p.Ser707Tyr取代位于对PLC γ 2激活至关重要的自身抑制性SH 2结构域中。改变的p.Ser707Tyr蛋白的过表达和使用受影响个体的白细胞的离体实验显示明显增强的PLC γ 2活性，表明PLC γ 2介导的途径中的细胞内信号传导增加。最近，我们的实验室在患有冷诱导的荨麻疹和免疫失调的个体中鉴定了PLCG 2外显子跳跃突变，导致蛋白质产物具有组成型磷脂酶活性，但在生理温度下细胞内信号传导减少。相比之下，PLC γ 2中的p.Ser707Tyr取代引起了一种独特的炎性表型，其不是由低温引起的，并且在生理温度下具有不同的终末器官参与和增加的细胞内信号传导。我们的研究结果强调了外显子组测序技术在发现显性遗传特征的核心家庭中的因果突变方面的实用性，否则连锁分析是难以解决的。
Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase C gamma 2 (PLC gamma 2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLC gamma 2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals' leukocytes showed clearly enhanced PLC gamma 2 activity, suggesting increased intracellular signaling in the PLC gamma 2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLC gamma 2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis.