Molecular and Phenotypic Characterization of Nine Patients with STAT1 GOF Mutations in China
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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.
We analyzed the clinical, molecular, and phenotypic characteristics of nine Chinese patients with STAT1 GOF mutations.
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.
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.
KeywordsSTAT1 gain-of-function innate immunity adaptive immunity
We thank the patients and their families for their kind cooperation in this study. We thank the members of the laboratory for technical assistance. We thank the doctors and nurses for supporting this project. We also thank Satoshi Okada for technical assistance.
XM.C., YF.A., and XD.Z. designed the study and wrote the manuscript; XM.C., L.Y., Z.C., T.Z., XH.X., T.X., YP.W., YJ.J., Q.Z., and JF.W. did the experiments and analyzed patients’ data; XM.C., QL.X., XL.L, LL.W., FF.L, J.Y, XM.T., and YF.A. followed the patients; all authors reviewed the manuscript before publication.
This work was supported by the Public Welfare Scientific Research Project of China (201402012).
Compliance with Ethical Standards
Informed consent was obtained from all individual participants included in the study. This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the ethics committee of Chongqing Medical University.
Conflict of Interest
The authors declare that they have no conflicts of interest.
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