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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

Chen, Yin Huai ; Grigelioniene, Giedre ; Newton, Phillip T. ; Gullander, Jacob LU ; Elfving, Maria LU ; Hammarsjö, Anna ; Batkovskyte, Dominyka ; Alsaif, Hessa S. ; Kurdi, Wesam I.Y. and Abdulwahab, Firdous , et al. (2020) In The Journal of experimental medicine 217(3).
Abstract

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... (More)

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.

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The Journal of experimental medicine
volume
217
issue
3
article number
e20191306
publisher
Rockefeller University Press
external identifiers
  • pmid:31914175
  • scopus:85077754381
ISSN
1540-9538
DOI
10.1084/jem.20191306
language
English
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yes
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9734b6a5-792e-4100-ad03-05fd6ecf672e
date added to LUP
2020-01-22 13:23:10
date last changed
2020-01-30 03:59:02
@article{9734b6a5-792e-4100-ad03-05fd6ecf672e,
  abstract     = {<p>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.</p>},
  author       = {Chen, Yin Huai and Grigelioniene, Giedre and Newton, Phillip T. and Gullander, Jacob and Elfving, Maria and Hammarsjö, Anna and Batkovskyte, Dominyka and Alsaif, Hessa S. and Kurdi, Wesam I.Y. and Abdulwahab, Firdous and Shanmugasundaram, Veerabahu and Devey, Luke and Bacrot, Séverine and Brodszki, Jana and Huber, Celine and Hamel, Ben and Gisselsson, David and Papadogiannakis, Nikos and Jedrycha, Katarina and Gürtl-Lackner, Barbara and Chagin, Andrei S. and Nishimura, Gen and Aschenbrenner, Dominik and Alkuraya, Fowzan S. and Laurence, Arian and Cormier-Daire, Valérie and Uhlig, Holm H.},
  issn         = {1540-9538},
  language     = {eng},
  number       = {3},
  publisher    = {Rockefeller University Press},
  series       = {The Journal of experimental medicine},
  title        = {Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome},
  url          = {http://dx.doi.org/10.1084/jem.20191306},
  doi          = {10.1084/jem.20191306},
  volume       = {217},
  year         = {2020},
}