Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3
Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3
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DOI：
10.1007/s10875-021-00975-y
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发表时间：
2021-01-26
影响因子：
9.1
通讯作者：
Kanegane, Hirokazu
中科院分区：
文献类型：
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作者：
Tanita, Kay;Sakura, Fumiaki;Kanegane, Hirokazu
目的信号转导子和转录激活子3（STAT3）基因的生殖系功能缺失变异导致常染色体显性高IgE综合征，而STAT3基因的体细胞功能获得性（GOF）变异与某些恶性肿瘤有关。此外，STAT3中的生殖系GOF变体与涉及自身免疫和淋巴细胞增殖的疾病有关。在这项研究中，我们描述了五个日本家庭与种系GOF变异的STAT3，包括三个新的变异。我们还介绍了这些患者的临床和免疫学特征。方法选取5个家系8例患者，进行回顾性分析。我们进行了遗传和免疫学分析，并收集了相关的临床信息。结果通过全外显子组测序和靶基因测序鉴定出5个STAT3杂合突变体。其中2个（E286 G和T716 M）为既往报告，3个（K348 E、E415 G和G618 A）为新发现。STAT3报告基因分析显示所有的变异体都是GOF。然而，患者的免疫学和临床特征是高度可变的。结论STAT3 GOF变异患者存在临床和免疫异质性，且不完全转化。
Purpose Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. Methods Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. Results We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. Conclusion Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.