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 ...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.展开更多
基金supported by funding from the Medical Research Council (MRC) through the WIMM Strategic Alliance (G0902418 and MC_UU_12025) and to E. Y.J. (G9900061),the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (AOMW)the Wellcome Trust (Project Grant 093329 to AOMW and SRFT+8 种基金Investigator Award 102731 to AOMWgrant 090532/Z/09/Z supporting the Wellcome Trust Centre for Human Genetics)supported by the Crohn’s & Colitis Foundation of America (CCFA)the Leona M. and Harry B. Helmsley Charitable Trustfunded by the NIHR Oxford Biomedical Research Centresupported by the Deutsche Forschungsgemeinschaft (SCHW1730/1-1)supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn (grant number SFB841 to F.K., D.S.-A., and S.R.-J.SFB877 to S.R.-J.)the Cluster of Excellence “Inflammation at Interfaces” to S.R.-J.
文摘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.
