Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.
Chen Y-H., Grigelioniene G., Newton PT., Gullander J., Elfving M., Hammarsjö A., Batkovskyte D., Alsaif HS., Kurdi WIY., Abdulwahab F., Shanmugasundaram V., Devey L., Bacrot S., Brodszki J., Huber C., Hamel B., Gisselsson D., Papadogiannakis N., Jedrycha K., Gürtl-Lackner B., Chagin AS., Nishimura G., Aschenbrenner D., Alkuraya FS., Laurence A., Cormier-Daire V., Uhlig HH.
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.