Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Rockefeller University Press
2020
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| _version_ | 1826265433123061760 |
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| author | Chen, Y Grigelioniene, G Newton, P Gullander, J Elfving, M Hammarsjö, A Batkovskyte, D Alsaif, H Kurdi, W Abdulwahab, F Shanmugasundaram, V Devey, L Bacrot, S Brodszki, J Huber, C Hamel, B Gisselsson, D Papadogiannakis, N Jedrycha, K Gürtl-Lackner, B Chagin, A Nishimura, G Aschenbrenner, D Alkuraya, F Laurence, A Cormier-Daire, V Uhlig, H |
| author_facet | Chen, Y Grigelioniene, G Newton, P Gullander, J Elfving, M Hammarsjö, A Batkovskyte, D Alsaif, H Kurdi, W Abdulwahab, F Shanmugasundaram, V Devey, L Bacrot, S Brodszki, J Huber, C Hamel, B Gisselsson, D Papadogiannakis, N Jedrycha, K Gürtl-Lackner, B Chagin, A Nishimura, G Aschenbrenner, D Alkuraya, F Laurence, A Cormier-Daire, V Uhlig, H |
| author_sort | Chen, Y |
| collection | OXFORD |
| description | The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development. |
| first_indexed | 2024-03-06T20:23:38Z |
| format | Journal article |
| id | oxford-uuid:2ea9a15c-6b74-4594-9612-16d12bf7a274 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:23:38Z |
| publishDate | 2020 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | oxford-uuid:2ea9a15c-6b74-4594-9612-16d12bf7a2742022-03-26T12:50:20ZAbsence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndromeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2ea9a15c-6b74-4594-9612-16d12bf7a274EnglishSymplectic Elements at OxfordRockefeller University Press2020Chen, YGrigelioniene, GNewton, PGullander, JElfving, MHammarsjö, ABatkovskyte, DAlsaif, HKurdi, WAbdulwahab, FShanmugasundaram, VDevey, LBacrot, SBrodszki, JHuber, CHamel, BGisselsson, DPapadogiannakis, NJedrycha, KGürtl-Lackner, BChagin, ANishimura, GAschenbrenner, DAlkuraya, FLaurence, ACormier-Daire, VUhlig, HThe gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development. |
| spellingShingle | Chen, Y Grigelioniene, G Newton, P Gullander, J Elfving, M Hammarsjö, A Batkovskyte, D Alsaif, H Kurdi, W Abdulwahab, F Shanmugasundaram, V Devey, L Bacrot, S Brodszki, J Huber, C Hamel, B Gisselsson, D Papadogiannakis, N Jedrycha, K Gürtl-Lackner, B Chagin, A Nishimura, G Aschenbrenner, D Alkuraya, F Laurence, A Cormier-Daire, V Uhlig, H Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title | Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title_full | Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title_fullStr | Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title_full_unstemmed | Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title_short | Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome |
| title_sort | absence of gp130 cytokine receptor signaling causes extended stuve wiedemann syndrome |
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