A variant in IL6ST with a selective IL-11 signaling defect in human and mouse
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
Abstract
Abstract 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 IL6ST (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 variant Il6st p.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 mice Il6st p.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 of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.