Abstract
The GP130 cytokine receptor subunit encoded byIL6STis the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant inIL6ST(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 variantIl6stp.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 miceIl6stp.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 ofIL11RAdeficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
ISSN: | 2095-4700 |
Language: | English |
Item ID: | 86042 |
Date Deposited: | 25. Jan 2022, 09:17 |
Last Modified: | 25. Jan 2022, 09:17 |