Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
J Clin Immunol. 2022 Nov;42(8):1778-1794. doi: 10.1007/s10875-022-01339-w. Epub 2022 Aug 17.
Mutations in signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) infection, which is attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency.
Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways.
Four, heterozygous STAT1 deficiency mutations were identified, three of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1-deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also intracellular non-mycobacterial bacterial infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ-mediated STAT1 phosphorylation, gamma-activated sequence (GAS), and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients.
The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host-pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity. Aberrant splice of STAT1 RNA could result in AD-LOF for STAT1 signaling which need more cases for confirmation.
信号转导子和转录激活子 1（STAT1）的突变导致广泛的疾病表型。STAT1 功能丧失（LOF）杂合突变导致孟德尔易感性分枝杆菌病（MSMD）感染，这归因于 IFN-γ 信号转导受损。新突变的鉴定可能会扩展与常染色体显性（AD）STAT1 缺乏相关的表型。
招募了 5 名具有杂合 STAT1 变异的患者，并分析了他们的临床和免疫表型，特别参考了 JAK-STAT1 信号通路。
鉴定出 4 种杂合 STAT1 缺陷突变，其中 3 种是新突变。两种突变是先前未报道的 AD STAT1 缺陷患者的 mRNA 剪接突变。杂合 STAT1 缺陷患者不仅患有分枝杆菌感染，还患有细胞内非分枝杆菌细菌感染和先天性多发性畸形。AD-LOF 突变不同程度地损害 IFN-γ 介导的 STAT1 磷酸化、γ-激活序列（GAS）和 IFN 刺激反应元件（ISRE）转录活性和 IFN 诱导的基因表达，这可能解释了这些患者观察到的不同临床表现。
AD STAT1-LOF 患者的感染性疾病易感性和表型谱比单纯的 MSMD 更广泛。AD-LOF 患者观察到的感染易感性和免疫缺陷表型证实了 STAT1 在宿主-病原体相互作用和免疫中的重要性。然而，这些表型的性质和程度的可变性表明需要进行功能分析以准确识别与致病性相关的新型杂合 STAT1 突变。STAT1 RNA 的异常剪接可能导致 STAT1 信号的 AD-LOF，需要更多病例来证实。
