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A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

         

摘要

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

著录项

  • 来源
    《骨研究:英文》 |2020年第2期|P.157-168|共12页
  • 作者单位

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UKDepartment of Pediatrics Dr von Hauner Children’s Hospital LMU Munich Munich Germany;

    Christian-Albrechts-University Kiel Institute of Biochemistry Kiel Germany;

    Clinical Genetics Group MRC Weatherall Institute of Molecular Medicine University of Oxford John Radcliffe Hospital Oxford UK;

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UK;

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UK;

    Center for Molecular Neurobiology Hamburg(ZMNH) University Medical Center Hamburg-Eppendorf Hamburg Germany;

    Christian-Albrechts-University Kiel Institute of Biochemistry Kiel GermanyThe Beatson Institute for Cancer Research Glasgow UK;

    Division of Structural Biology Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK;

    Christian-Albrechts-University Kiel Institute of Biochemistry Kiel Germany;

    Craniofacial Unit Department of Plastic and Reconstructive Surgery Oxford University Hospitals NHS Foundation Trust John Radcliffe Hospital Oxford UK;

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UKSchool of Medicine University of Glasgow Glasgow UK;

    Section Biomedical Imaging Department of Radiology and Neuroradiology University Medical Center Schleswig-Holstein Kiel Germany;

    Section Biomedical Imaging Department of Radiology and Neuroradiology University Medical Center Schleswig-Holstein Kiel Germany;

    Institute of Biochemistry and Molecular Biology Ⅱ Medical Faculty Heinrich-Heine-University Düsseldorf Germany;

    Christian-Albrechts-University Kiel Institute of Biochemistry Kiel Germany;

    Division of Structural Biology Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK;

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UK;

    Clinical Genetics Group MRC Weatherall Institute of Molecular Medicine University of Oxford John Radcliffe Hospital Oxford UKCraniofacial Unit Department of Plastic and Reconstructive Surgery Oxford University Hospitals NHS Foundation Trust John Radcliffe Hospital Oxford UK;

    Christian-Albrechts-University Kiel Institute of Biochemistry Kiel Germany;

    Translational Gastroenterology Unit John Radcliffe Hospital University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKNIHR Oxford Biomedical Research Centre Oxford UK;

  • 原文格式 PDF
  • 正文语种 chi
  • 中图分类 骨科学(运动系疾病、矫形外科学);
  • 关键词

    IL11; cytokine; facial;

    机译:IL11;细胞因子;面部;
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