Journal Article

A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

Jung, Jonathan, Wilkie Andrew O M, Twigg Stephen R F, Borgmeyer Uwe, Wall, Steven A, Schwerd Tobias, Chen Yin-Huai, Aschenbrenner Dominik, Schmidt-Arras, Dirk, Damm Timo, Uhlig, Holm H, Scheller Jürgen, Manrique, Santiago, Yvonne, Jones E, Schumacher Neele, Claus-Christian, Glüer, Arian, Laurence, Krause Freia, Müller Miryam, Rose-John, Stefan

2020

Overview

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.

• Publisher: Springer Nature B.V
• Subject: Cytokines