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- Title
A variant in IL6ST with a selective IL-11 signaling defect in human and mouse.
- Authors
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; Glüer, Claus-Christian; Scheller, Jürgen; Rose-John, Stefan; Jones, E. Yvonne; Laurence, Arian; Wilkie, Andrew O. M.; Schmidt-Arras, Dirk; Uhlig, Holm H.
- 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.
- Subjects
CYTOKINE receptors; INTERLEUKIN-11; CRANIOSYNOSTOSES; CELLULAR signal transduction; LABORATORY mice
- Publication
Bone Research, 2020, Vol 8, Issue 1, p1
- ISSN
2095-4700
- Publication type
Article
- DOI
10.1038/s41413-020-0098-z