Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.
Antigens, CD
/ metabolism
Cells, Cultured
Cytokine Receptor gp130
/ metabolism
Exostoses, Multiple Hereditary
/ metabolism
HEK293 Cells
Humans
Interleukin-11
/ metabolism
Interleukin-6
/ metabolism
Leukemia Inhibitory Factor
/ metabolism
Oncostatin M
/ metabolism
Osteochondrodysplasias
/ metabolism
Receptors, Cytokine
/ metabolism
Signal Transduction
/ physiology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 03 2020
02 03 2020
Historique:
received:
15
07
2019
revised:
07
10
2019
accepted:
14
11
2019
entrez:
9
1
2020
pubmed:
9
1
2020
medline:
31
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31914175
pii: 133568
doi: 10.1084/jem.20191306
pmc: PMC7062520
pii:
doi:
Substances chimiques
Antigens, CD
0
Interleukin-11
0
Interleukin-6
0
Leukemia Inhibitory Factor
0
Receptors, Cytokine
0
Oncostatin M
106956-32-5
Cytokine Receptor gp130
133483-10-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2020 Chen et al.
Déclaration de conflit d'intérêts
Disclosures: Dr. Chen reported grants from Celgene during the conduct of the study and grants from Celgene outside the submitted work. Dr. Devey is an employee and stockholder of Celgene and is a former employee and stockholder of GlaxoSmithKline. Dr. Shanmugasundaram is an employee and stockholder of Celgene and a stockholder of Pfizer. Celgene has now become a wholly-owned subsidiary of Bristol-Myers Squibb. Dr. Aschenbrenner reported grants from UCB Pharma GmbH and grants from Eli Lilly and Company outside the submitted work. Dr. Uhlig reported grants from Celgene during the conduct of the study, grants from UCB Pharma, grants from Eli Lilly, personal fees from AbbVie, personal fees from Pfizer, and "other" from Regeneron outside the submitted work. No other disclosures were reported.
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