학술논문
Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
Document Type
Article
Author
Chen, Yin-Huai; Grigelioniene, Giedre; Newton, Phillip T.; Gullander, Jacob; Elfving, Maria; Hammarsjö, Anna; Batkovskyte, Dominyka; Alsaif, Hessa S.; Kurdi, Wesam I.Y.; Abdulwahab, Firdous; Shanmugasundaram, Veerabahu; Devey, Luke; Bacrot, Séverine; Brodszki, Jana; Huber, Celine; Hamel, Ben; Gisselsson, David; Papadogiannakis, Nikos; Jedrycha, Katarina; Gürtl-Lackner, Barbara; Chagin, Andrei S.; Nishimura, Gen; Aschenbrenner, Dominik; Alkuraya, Fowzan S.; Laurence, Arian; Cormier-Daire, Valérie; Uhlig, Holm H.
Source
The Journal of Experimental Medicine; March 2020, Vol. 217 Issue: 3 pe20191306-e20191306, 1p
Subject
Language
ISSN
00221007; 15409538
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 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.