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  • 제25권2호
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  • Pages.18.1-18.2
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  • 2025
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Novel STAT3 Y360C Gain-of-function Variant Underlies Immune Dysregulation and Aberrancy in Mitochondrial Dynamics

  • Kornvalee Meesilpavikkai (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Kasiphak Kaikaew (Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University) ;
  • Zijun Zhou (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Virgil A.S.H. Dalm (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Fabian M.P. Kaiser (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Christopher Schliehe (Department of Immunology, Erasmus University Medical Center) ;
  • Sigrid M.A. Swagemakers (Department of Pathology and Bioinformatics, Erasmus University Medical Center) ;
  • Peter J. van der Spek (Department of Pathology and Bioinformatics, Erasmus University Medical Center) ;
  • Benjamin Schrijver (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Pamela Vasic (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Maaike de Bie (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Marleen Bakker (Department of Pulmonary Medicine, Erasmus Medical Center) ;
  • Chiara Milanese (Department of Molecular Genetics, Erasmus University Medical Center) ;
  • Pier G. Mastroberardino (Department of Molecular Genetics, Erasmus University Medical Center) ;
  • Nattiya Hirankarn (Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University) ;
  • Narissara Suratannon (Division of Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University) ;
  • Hanna IJspeert (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • Willem A. Dik (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center) ;
  • P. Martin van Hagen (Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center)
  • 투고 : 2024.10.27
  • 심사 : 2025.03.12
  • 발행 : 2025.04.30
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초록

The STAT3 is an important regulator in a wide range of different cell types. Human STAT3 variants are associated with several immune dysregulation diseases. The current study investigated the clinical, genetic, and immunobiological data obtained from a family with novel heterozygous STAT3 variants located at p.Y360C of the DNA binding domain. The clinical manifestations of these patients include autoimmunity, immunodeficiency, and postnatal growth defects. Broad STAT3 regulated cells including patient primary immune cells and HEK293 cells harboring the variant were assessed. Remarkably high levels of STAT3-regulated cytokines were detected in the sera of the patients. STAT3 nuclear binding and STAT3 activity were higher in STAT3-transduced HEK293 cells containing the p.Y360C variant when compared to HEK cells expressing wild type (WT) STAT3. Upon cytokine activation, STAT3 variants inhibited nuclear translocation of the WT STAT3 molecule. We also demonstrated that PBMCs from these patients exhibit significantly higher mitochondrial activity compared to that of healthy controls. The exploration of the effects of STAT3 Y360C variants described in our study provides novel insights into the molecular effects of the STAT3 variant and its role in the pathophysiology of STAT3 gain-of-function syndromes.

키워드

과제정보

The work in this manuscript has been supported by Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation (OPS MHESI), Thailand Science Research and Innovation (TSRI) (Grant No. RGNS 64-002), the NSRF via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation (Grant No. B16F640154), Rachadapisek Sompote Matching Fund (RA-MF-04/68), Rachadapisek Sompote Matching Fund (RA-MF-07/66), Faculty of Medicine, Chulalongkorn University, National Research Council of Thailand (NRCT) and Chulalongkorn University (N42A680063), Stichting Sophia Kinderziekenhuis Fonds (Grant No. S15-07). Erasmus MC, University Medical Center Rotterdam, the Netherlands, and the China Scholarship Council for funding PhD fellowships (No. 201908440363 Z.Z).

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