A patient-based murine model recapitulates human STAT3 gain-of-function syndrome

Kornvalee Meesilpavikkai; Zijun Zhou; Kasiphak Kaikaew; Suphattra Phakham; Peter J van der Spek; Sigrid Swagemakers; Deon J Venter; Maaike de Bie; Benjamin Schrijver; Christopher Schliehe; Fabian Kaiser; Virgil A S H Dalm; P Martin van Hagen; Nattiya Hirankarn; Hanna IJspeert; Willem A Dik

doi:10.1016/j.clim.2024.110312

A patient-based murine model recapitulates human STAT3 gain-of-function syndrome

Clin Immunol. 2024 Sep:266:110312. doi: 10.1016/j.clim.2024.110312. Epub 2024 Jul 15.

Authors

Kornvalee Meesilpavikkai¹, Zijun Zhou², Kasiphak Kaikaew³, Suphattra Phakham⁴, Peter J van der Spek⁵, Sigrid Swagemakers⁵, Deon J Venter⁶, Maaike de Bie⁷, Benjamin Schrijver², Christopher Schliehe⁸, Fabian Kaiser⁸, Virgil A S H Dalm⁹, P Martin van Hagen¹⁰, Nattiya Hirankarn¹¹, Hanna IJspeert⁷, Willem A Dik¹²

Affiliations

¹ Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
² Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
³ Center of Excellence in Alternative and Complementary Medicine of Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁴ Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁵ Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁶ Department of Pathology, Mater Health Services, Brisbane, Queensland, Australia.
⁷ Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸ Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁹ Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁰ Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: [email protected].
¹¹ Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address: [email protected].
¹² Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: [email protected].

PMID: 39019339
DOI: 10.1016/j.clim.2024.110312

Abstract

STAT3 gain-of-function (GOF) variants results in a heterogeneous clinical syndrome characterized by early onset immunodeficiency, multi-organ autoimmunity, and lymphoproliferation. While 191 documented cases with STAT3 GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a Stat3^p.L387R mouse model, mirroring a variant identified in a family exhibiting common STAT3 GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. In vitro experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our Stat3^p.L387R model displayed similar traits from previous Stat3^GOF strains, such as splenomegaly and lymphadenopathy. Notably, Stat3^p.L387R/+ mice exhibited heightened embryonic lethality compared to prior Stat3^GOF/+ models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3^p.L387R/+ mice, highlighting the ability to recapitulate human STAT3 GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.

Keywords: Autoimmunity; Immune regulatory disorders; Immunodeficiency; Patient-specific variants; STAT3 GOF syndrome; Transgenic mouse model.

MeSH terms

Animals
Disease Models, Animal*
Female
Gain of Function Mutation* / genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Phosphorylation
STAT3 Transcription Factor* / genetics
STAT3 Transcription Factor* / metabolism

Substances

STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, mouse