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J Clin Immunol. 2019 Nov 4. doi: 10.1007/s10875-019-00688-3. [Epub ahead of print]

Molecular and Phenotypic Characterization of Nine Patients with STAT1 GOF Mutations in China.

Chen X1,2, Xu Q1,2, Li X3, Wang L4, Yang L1,2, Chen Z1,2, Zeng T1,2, Xue X1,2, Xu T1,2, Wang Y1,2, Jia Y1,2, Zhao Q1,2, Wu J5, Liang F1,2, Tang X5, Yang J4, An Y6,7,8, Zhao X9,10,11.

Author information

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.

KEYWORDS:

STAT1; adaptive immunity; gain-of-function; innate immunity

PMID:
31686315
DOI:
10.1007/s10875-019-00688-3

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