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

doi:10.1038/s41413-020-0098-z

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

Bone Res. 2020 Jun 11:8:24. doi: 10.1038/s41413-020-0098-z. eCollection 2020.

Authors

Tobias Schwerd^#^{1

2}, Freia Krause^#³, Stephen R F Twigg^#⁴, Dominik Aschenbrenner¹, Yin-Huai Chen¹, Uwe Borgmeyer⁵, Miryam Müller^{3

6}, Santiago Manrique⁷, Neele Schumacher³, Steven A Wall⁸, Jonathan Jung^{1

9}, Timo Damm¹⁰, Claus-Christian Glüer¹⁰, Jürgen Scheller¹¹, Stefan Rose-John³, E Yvonne Jones⁷, Arian Laurence¹, Andrew O M Wilkie^#^{4

8}, Dirk Schmidt-Arras^#³, Holm H Uhlig^#^{1

12

13}

Affiliations

¹ Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
² Department of Pediatrics, Dr von Hauner Children's Hospital, LMU Munich, Munich, Germany.
³ Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany.
⁴ Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
⁵ Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Present Address: The Beatson Institute for Cancer Research, Glasgow, UK.
⁷ Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸ Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
⁹ Present Address: School of Medicine, University of Glasgow, Glasgow, UK.
¹⁰ Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹¹ Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹² Department of Paediatrics, University of Oxford, Oxford, UK.
¹³ NIHR Oxford Biomedical Research Centre, Oxford, UK.

^# Contributed equally.

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.

Keywords: Bone; Pathogenesis.

Abstract

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