Novel STAT3 Y360C Gain-of-function Variant Underlies Immune Dysregulation and Aberrancy in Mitochondrial Dynamics

• DOI: 10.4110/in.2025.25.e18
• Publication Date: 2025-04-30T06:47:40Z
• Authors: Kornvalee Meesilp...; Kasiphak Kaikaew; Zijun Zhou; Virgil A.S.H. Dalm; Fabian M.P. Kaiser; Christopher Schliehe; Sigrid M.A. Swage...; Peter J. van der ...; Benjamin Schrijver; Pamela Vasic; Maaike de Bie; Marleen Bakker; Chiara Milanese; Pier G. Mastrober...; Nattiya Hirankarn; Narissara Suratannon; Hanna IJspeert; Willem A. Dik; P. Martin van Hagen
• Keywords: Gain of function; Immune Dysregulation; Immune escape

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