A variant in IL6ST with a selective IL-11 signaling defect in human and mouse
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...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Springer Nature
2020
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| _version_ | 1826279209649045504 |
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| author | Schwerd, T Krause, F Twigg, S Manrique Zuniga, S Jones, EY Wilkie, A Uhlig, |
| author_facet | Schwerd, T Krause, F Twigg, S Manrique Zuniga, S Jones, EY Wilkie, A Uhlig, |
| author_sort | Schwerd, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:55:21Z |
| format | Journal article |
| id | oxford-uuid:74067150-26b3-4bf9-bd2b-bf2d7252cbef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:55:21Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:74067150-26b3-4bf9-bd2b-bf2d7252cbef2022-03-26T20:00:10ZA variant in IL6ST with a selective IL-11 signaling defect in human and mouseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:74067150-26b3-4bf9-bd2b-bf2d7252cbefEnglishSymplectic ElementsSpringer Nature2020Schwerd, TKrause, FTwigg, SManrique Zuniga, SJones, EYWilkie, AUhlig,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. |
| spellingShingle | Schwerd, T Krause, F Twigg, S Manrique Zuniga, S Jones, EY Wilkie, A Uhlig, A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title_full | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title_fullStr | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title_full_unstemmed | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title_short | A variant in IL6ST with a selective IL-11 signaling defect in human and mouse |
| title_sort | variant in il6st with a selective il 11 signaling defect in human and mouse |
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