A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

Abstract

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

“…The fact that Il11 -/mice do not have snout deformities implies that this is unrelated to the loss of IL11 signaling per se. However, a biallelic non-synonymous variant in IL6ST , which results in a selective loss of IL11-signaling, conferred a craniosynostosis phenotype, which replicated in a mouse model 18 . Intriguingly, while LOF mutations in IL11 are common in the general population they have not been associated with craniosynostosis despite large scale sequencing projects 7 whereas IL11RA mutations are widely reported 5,6 .…”

A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling

“…However, we cannot rule out that N114L in isolation would also show a discriminatory effect with regard to the inhibition of IL-11 trans-signaling. Interestingly, the gp130 mutation R281Q mutation in a patient with craniosynostosis has been described, which leads to a selective loss of IL-11 signaling ( Schwerd et al., 2020 ). It is tempting to speculate that the introduction of the mutations described in this study into membrane-bound gp130 would result in a similar effect.…”

Insights and future directions of potential genetic therapy for Apert syndrome: A systematic review

“…Knowledge of the normal and pathological process of cranial development is essential for addressing the abnormality in the complex molecular signalling pathways, and its consequences towards tissue development. Similarities in craniofacial development and its molecular pathway have been found between mouse and human, making mouse as the ideal model for craniosynostosis study because of the genetic and physiological similarities between the species (31)(32)(33). Therefore, many in vivo studies used mice models to allow the induction of cranial suture fusion and imitating the actual human craniosynostosis in AS.…”