Mutations in craniosynostosis patients cause defective Interleukin-11 receptor maturation and drive craniosynostosis-like disease in mice
- Author(s)
- Agthe, M; Brugge, J; Garbers, Y; Wandel, M; Kespohl, B; Arnold, P; Flynn, CM; Lokau, J; Aparicio-Siegmund, S; Bretscher, C; Rose-John, S; Waetzig, GH; Putoczki, T; Grotzinger, J; Garbers, C;
- Details
- Publication Year 2018-10-02,Volume 25,Issue #1,Page 10-18 e5
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- Abstract
- Premature closure of the sutures that connect the cranial bones during development of the mammalian skull results in a phenotype called craniosynostosis. Recently, several craniosynostosis patients with missense mutations within the gene encoding the interleukin-11 receptor (IL-11R) have been described, but the underlying molecular mechanisms have remained elusive. IL-11 is a cytokine that has a crucial role in bone remodeling and activates cells via binding to the IL-11R. Here, we show that patient mutations prevented maturation of the IL-11R, resulting in endoplasmic reticulum retention and diminished cell surface appearance. Disruption of a conserved tryptophan-arginine zipper within the third domain of the IL-11R was the underlying cause of the defective maturation. IL-11 classic signaling via the membrane-bound receptor, but not IL-11 trans-signaling via the soluble receptor, was the crucial pathway for normal skull development in mice in vivo. Thus, the specific therapeutic inhibition of IL-11 trans-signaling does not interfere with skull development.
- Publisher
- Cell Press
- Research Division(s)
- Inflammation
- PubMed ID
- 30282020
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2018.09.005
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2018.09.005- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-10-11 04:23:11
Last Modified: 2018-10-12 11:54:02