Q1 · MEDICINE
Article
Author: Hamel, Ben ; Shanmugasundaram, Veerabahu ; Nishimura, Gen ; Gisselsson, David ; Gullander, Jacob ; Chagin, Andrei S. ; Jedrycha, Katarina ; Abdulwahab, Firdous ; Batkovskyte, Dominyka ; Aschenbrenner, Dominik ; Alkuraya, Fowzan S. ; Newton, Phillip T. ; Laurence, Arian ; Chen, Yin-Huai ; Bacrot, Séverine ; Grigelioniene, Giedre ; Elfving, Maria ; Uhlig, Holm H. ; Brodszki, Jana ; Devey, Luke ; Huber, Celine ; Papadogiannakis, Nikos ; Kurdi, Wesam I.Y. ; Gürtl-Lackner, Barbara ; Alsaif, Hessa S. ; Hammarsjö, Anna ; Cormier-Daire, Valérie
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.