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

Tobias Schwerd ,Freia Krause ,Santiago Manrique ,Timo Damm ,Neele Schumacher ,Jonathan Jung ,Y-H Chen ,Twigg Srf ,Elizabeth Jones ,Uwe Borgmeyer ,Jürgen Scheller ,Glüer C-C ,Dominik Aschenbrenner ,Dirk Schmidt-Arras ,Wilkie Aom ,Stefan Rose‐John ,Steven A Wall ,Arian Laurence ,Miryam Müller ,Holm H Uhlig

doi:10.1038/s41413-020-0098-z

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.

Highlights

GP130 is the common receptor subunit for the family of interleukin (IL)-6 cytokines that includes IL-6, IL-11, IL-27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT1), and cardiotrophin-like cytokine (CLC).[1]
To allow specificity of cytokine receptor binding in different cell types, GP130 forms a multimeric complex on the cell surface with cytokineselective receptor subunits that are either signaling-incompetent such as IL6RA, IL11RA, CNTFR, or signaling competent such as LIFR, OSMR, or IL-27R facilitating downstream activation of cytoplasmic tyrosine kinases which phosphorylate STAT3 and STAT1 or activate the RAS/MAPK pathway.[1]
We have recently described patients with severe immunodeficiency and skeletal abnormalities, such as severe craniosynostosis and progressive scoliosis caused by recessive partial loss-of-function variants in IL6ST, encoding GP130.19,20

Summary

1234567890();,: INTRODUCTION

GP130 is the common receptor subunit for the family of interleukin (IL)-6 cytokines that includes IL-6, IL-11, IL-27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT1), and cardiotrophin-like cytokine (CLC).[1]. Craniosynostosis and delayed tooth eruption observed in individuals with IL11RA mutations, likely result from reduced bone resorption at sutures or in the jaw, as it has been shown that IL11RA-deficient mice display decreased bone resorption in long bones.[6] We have recently described patients with severe immunodeficiency and skeletal abnormalities, such as severe craniosynostosis and progressive scoliosis caused by recessive partial loss-of-function variants in IL6ST, encoding GP130 (hyper-IgE recurrent infection syndrome 4, autosomal recessive; MIM 618523).[19,20] Detailed functional studies demonstrated that different homozygous non-synonymous variants had These authors contributed : Tobias Schwerd, Freia Krause, Stephen R. Enriched in individuals of South Asian origin (minor allele frequency 0.001 5), (c) the mother of PR281Q, herself the offspring of consanguineous parents, was homozygous for the same variant (Fig. 1a) but without any history of craniofacial or severe tooth

RESULTS

28 IL-27 21

20 IL6RA f GP130-Ypet

Findings

11 AUTHOR CONTRIBUTIONS