Xuemei Chen1,2, Qiling Xu1,2, Xiaolin Li3, Linlin Wang4, Lu Yang1,2, Zhi Chen1,2, Ting Zeng1,2, Xiuhong Xue1,2, Tao Xu1,2, Yanping Wang1,2, Yanjun Jia1,2, Qin Zhao1,2, Junfeng Wu5, Fangfang Liang1,2, Xuemei Tang5, Jun Yang4, Yunfei An6,7,8, Xiaodong Zhao9,10,11. 1. 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, People's Republic of China. 2. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. 3. Department of Pediatric Rheumatology and Immunology, Zhongshan Boai Hospital Affiliated Southern Medical University, Zhongshan, 528400, China. 4. Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, 518000, China. 5. Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. 6. 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, People's Republic of China. anyf82@aliyun.com. 7. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. anyf82@aliyun.com. 8. Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. anyf82@aliyun.com. 9. 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, People's Republic of China. zhaoxd530@aliyun.com. 10. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. zhaoxd530@aliyun.com. 11. Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. zhaoxd530@aliyun.com.
Abstract
PURPOSE: Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates cellular responses to interferons (IFNs) and other cytokines and growth factors in diverse cell types. STAT1 gain-of-function (GOF) mutations result in an unexpectedly wide range of clinical features. It remains unclear why STAT1 GOF mutations result in such a broad spectrum of phenotypes. METHODS: We analyzed the clinical, molecular, and phenotypic characteristics of nine Chinese patients with STAT1 GOF mutations. RESULTS: This study enrolled nine patients with STAT1 GOF mutations including five novel mutations. We discuss the molecular and phenotypic characterization such as unique Penicillium marneffei lymphadenitis. Patients with STAT1 GOF mutations had defects in both innate and adaptive immunity, including impaired T cell receptor (TCR) diversity; reduced numbers of naïve and effector memory CD4+ T cells, memory B cells, and NK cells; and defects in the production of IL-17A and IFN-γ. In addition, experiments with primary immune cells revealed that enhanced STAT1 phosphorylation resulted from not only lower rates of STAT1 dephosphorylation but also increased total STAT1 expression. CONCLUSIONS: Our report provides the first comprehensive overview of the molecular genetics, clinical heterogeneity, and underlying immunological abnormalities of patients with STAT1 GOF mutations in China. In further study, to find the relationship between different STAT1 GOF mutations and clinical phenotype as well as the mechanism of increased total STAT1 expression will be needed.
PURPOSE:Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates cellular responses to interferons (IFNs) and other cytokines and growth factors in diverse cell types. STAT1 gain-of-function (GOF) mutations result in an unexpectedly wide range of clinical features. It remains unclear why STAT1 GOF mutations result in such a broad spectrum of phenotypes. METHODS: We analyzed the clinical, molecular, and phenotypic characteristics of nine Chinese patients with STAT1 GOF mutations. RESULTS: This study enrolled nine patients with STAT1 GOF mutations including five novel mutations. We discuss the molecular and phenotypic characterization such as unique Penicillium marneffeilymphadenitis. Patients with STAT1 GOF mutations had defects in both innate and adaptive immunity, including impaired T cell receptor (TCR) diversity; reduced numbers of naïve and effector memory CD4+ T cells, memory B cells, and NK cells; and defects in the production of IL-17A and IFN-γ. In addition, experiments with primary immune cells revealed that enhanced STAT1 phosphorylation resulted from not only lower rates of STAT1 dephosphorylation but also increased total STAT1 expression. CONCLUSIONS: Our report provides the first comprehensive overview of the molecular genetics, clinical heterogeneity, and underlying immunological abnormalities of patients with STAT1 GOF mutations in China. In further study, to find the relationship between different STAT1 GOF mutations and clinical phenotype as well as the mechanism of increased total STAT1 expression will be needed.
Authors: Jacob M Rosenberg; Joshua M Peters; Travis Hughes; Caleb A Lareau; Leif S Ludwig; Lucas R Massoth; Christina Austin-Tse; Heidi L Rehm; Bryan Bryson; Yi-Bin Chen; Aviv Regev; Alex K Shalek; Sarah M Fortune; David B Sykes Journal: Med (N Y) Date: 2022-01-14
Authors: Ori Scott; Kyle Lindsay; Steven Erwood; Antonio Mollica; Chaim M Roifman; Ronald D Cohn; Evgueni A Ivakine Journal: NPJ Genom Med Date: 2021-05-14 Impact factor: 8.617
Authors: Amalia Lamana; Ricardo Villares; Iria V Seoane; Nuria Andrés; Pilar Lucas; Paul Emery; Edward M Vital; Ana Triguero-Martínez; Ana Marquez; Ana M Ortiz; Robin Maxime; Carmen Martínez; Javier Martín; Rosa P Gomariz; Frederique Ponchel; Isidoro González-Álvaro; Mario Mellado Journal: Front Immunol Date: 2020-06-26 Impact factor: 8.786