| 5 | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse显示文摘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. | Tobias Schwerd Freia Krause Stephen R.F.Twigg Dominik Aschenbrenner Yin-Huai Chen Uwe Borgmeyer Miryam Müller Santiago Manrique Neele Schumacher Steven A.Wall Jonathan Jung Timo Damm Claus-Christian Glüer Jürgen Scheller Stefan Rose-John E.Yvonne Jones Arian Laurence Andrew O.M.Wilkie Dirk Schmidt-Arras Holm H.Uhlig | 2020 | Bone Research2020，8，2： | 0 |
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