Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice.

Authors:
Maria Agthe, Julian Brügge, Yvonne Garbers, Marieke Wandel, Birte Kespohl, Philipp Arnold, Charlotte M Flynn, Juliane Lokau, Samadhi Aparicio-Siegmund, Christian Bretscher, Stefan Rose-John, Georg H Waetzig, Tracy Putoczki, Joachim Grötzinger, Christoph Garbers
Year of publication:
2018
Volume:
25
Issue:
1
Issn:
2211-1247
Journal title abbreviated:
CELL REP
Journal title long:
Cell reports
Impact factor:
8.109
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.