Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes

作者全名："Chen, Xuemei; Chen, Junjie; Chen, Ran; Mou, Huilin; Sun, Gan; Yang, Lu; Jia, Yanjun; Zhao, Qin; Wen, Wen; Zhou, Lina; Ding, Yuan; Tang, Xuemei; Yang, Jun; An, Yunfei; Zhao, Xiaodong"

作者地址："[Chen, Xuemei; Chen, Junjie; Chen, Ran; Mou, Huilin; Sun, Gan; Yang, Lu; Jia, Yanjun; Zhao, Qin; Wen, Wen; Zhou, Lina; Ding, Yuan; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp,Natl Clin Res Ctr Child Hlth & Dis, Dept Pediat,Key Lab Child Dev & Disorders, Res Inst,Minist Educ,China Int Sci & Technol Coop, Chongqing, Peoples R China; [Chen, Xuemei; Chen, Junjie; Chen, Ran; Mou, Huilin; Sun, Gan; Yang, Lu; Jia, Yanjun; Zhao, Qin; Wen, Wen; Zhou, Lina; Ding, Yuan; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing 400014, Peoples R China; [Tang, Xuemei; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Dept Rheumatol & Immunol, Chongqing 400014, Peoples R China; [Yang, Jun] Shenzhen Childrens Hosp, Dept Rheumatol & Immunol, Shenzhen 518000, Peoples R China"

通信作者："An, YF; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp,Natl Clin Res Ctr Child Hlth & Dis, Dept Pediat,Key Lab Child Dev & Disorders, Res Inst,Minist Educ,China Int Sci & Technol Coop, Chongqing, Peoples R China.; An, YF; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing 400014, Peoples R China.; An, YF; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Rheumatol & Immunol, Chongqing 400014, Peoples R China."

来源：JOURNAL OF CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000842576900001

JCR分区：Q1

影响因子：9.1

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：STAT1; Autosomal dominant; Loss-of-function; Diverse clinical; Immunologic phenotypes

摘要："Purpose 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-gamma signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency. Methods Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways. Results 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-gamma-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. Conclusion 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."

基金机构：Natural Science Foundation of China [81620108014]; National High Technology Research and Development Program of China [2021YFC2700804]

基金资助正文："This work was supported by the Natural Science Foundation of China (Grant Number 81620108014), and the National High Technology Research and Development Program of China (Grant Number 2021YFC2700804)."