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

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 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 model displayed similar traits from previous Stat3 strains, such as splenomegaly and lymphadenopathy. Notably, Stat3 mice exhibited heightened embryonic lethality compared to prior Stat3 models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3 mice, highlighting the ability to recapitulate human STAT3 GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.