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
{"title":"A patient-based murine model recapitulates human STAT3 gain-of-function syndrome","authors":"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","DOIUrl":null,"url":null,"abstract":"<div><p>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 <em>STAT3</em> GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a <em>Stat3</em><sup>p.L387R</sup> mouse model, mirroring a variant identified in a family exhibiting common <em>STAT3</em> GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. <em>In vitro</em> experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our <em>Stat3</em><sup>p.L387R</sup> model displayed similar traits from previous <em>Stat3</em><sup>GOF</sup> strains, such as splenomegaly and lymphadenopathy. Notably, <em>Stat3</em><sup>p.L387R/+</sup> mice exhibited heightened embryonic lethality compared to prior <em>Stat3</em><sup>GOF/+</sup> models and ocular abnormalities were observed. This research underscores the variant-specific pathology in <em>Stat3</em><sup>p.L387R/+</sup> mice, highlighting the ability to recapitulate human <em>STAT3</em> GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"266 ","pages":"Article 110312"},"PeriodicalIF":4.5000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1521661624004212","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
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 Stat3p.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 Stat3p.L387R model displayed similar traits from previous Stat3GOF strains, such as splenomegaly and lymphadenopathy. Notably, Stat3p.L387R/+ mice exhibited heightened embryonic lethality compared to prior Stat3GOF/+ models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3p.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.
期刊介绍:
Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.