A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.
Schwerd T., Twigg SRF., Aschenbrenner D., Manrique S., Miller KA., Taylor IB., Capitani M., McGowan SJ., Sweeney E., Weber A., Chen L., Bowness P., Riordan A., Cant A., Freeman AF., Milner JD., Holland SM., Frede N., Müller M., Schmidt-Arras D., Grimbacher B., Wall SA., Jones EY., Wilkie AOM., Uhlig HH.
Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.