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Schwerd, Tobias; Krause, Freia; Twigg, Stephen R. F.; Aschenbrenner, Dominik; Chen, Yin-Huai; Borgmeyer, Uwe; Müller, Miryam; Manrique, Santiago; Schumacher, Neele; Wall, Steven A.; Jung, Jonathan; Damm, Timo; Glueer, Claus-Christian; Scheller, Jürgen; Rose-John, Stefan; Jones, E. Yvonne; Laurence, Arian; Wilkie, Andrew O. M.; Schmidt-Arras, Dirk and Uhlig, Holm H. (2020): A variant in IL6ST with a selective IL-11 signaling defect in human and mouse. In: Bone Research, Vol. 8, No. 1, 24

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The GP130 cytokine receptor subunit encoded byIL6STis the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant inIL6ST(p.R281Q) 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 variantIl6stp.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In miceIl6stp.R279Q 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 ofIL11RAdeficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

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