Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations
Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations
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DOI：
10.1093/intimm/dxaa043
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发表时间：
2020-10-01
影响因子：
4.4
通讯作者：
Okada, Satoshi
中科院分区：
文献类型：
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作者：
Sakata, Sonoko;Tsumura, Miyuki;Okada, Satoshi
常染色体隐性 (AR) 完全信号转导子和转录激活子 1 (STAT1) 缺陷是一种极其罕见的原发性免疫缺陷，可导致危及生命的分枝杆菌和病毒感染。迄今为止，只有来自五个无关家庭的七名患者患有这种疾病。报告的所有 STAT1 因果突变都是外显子和纯合的。我们研究了一名对分枝杆菌和病毒感染易感的患者，结果鉴定出由于复合杂合突变而导致 AR 完全 STAT1 缺陷，这两种突变均位于内含子中：c.128+2 T>G 和 c.542-8 A>G。这两种突变都是第一个导致 AR 完全 STAT1 缺陷的内含子 STAT1 突变。靶向 RNA-seq 记录了 STAT1 mRNA 表达的损伤，并有助于识别内含子突变。患者的细胞缺乏 STAT1 表达和磷酸化，并且细胞对 IFN-γ 和 IFN-α 的反应严重受损。该病例反映了当患者缺乏分子发病机制时，在全面的基因组研究中准确的临床诊断和精确的评估（包括内含子突变）的重要性。总之，AR完全STAT1缺陷可能是由复合杂合和内含子突变引起的。基于RNA-seq的靶向系统基因表达检测可能有助于在全面的基因组研究后提高不确定病例的诊断率。
Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T>G and c.542-8 A>G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient's cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-gamma and IFN-alpha. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations.Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.