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Cell Rep. 2018 Oct 2;25(1):10-18.e5. doi: 10.1016/j.celrep.2018.09.005.

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

Author information

1
Institute of Biochemistry, Kiel University, Kiel, Germany.
2
Institute of Psychology, Kiel University, Kiel, Germany.
3
Institute of Anatomy, Kiel University, Kiel, Germany.
4
CONARIS Research Institute AG, Kiel, Germany.
5
The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
6
Institute of Biochemistry, Kiel University, Kiel, Germany. Electronic address: christoph.garbers@med.ovgu.de.

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.

KEYWORDS:

craniosynostosis; development; endoplasmic reticulum; gp130; interleukin-11; interleukin-6; osteoclast; trans-signaling

PMID:
30282020
DOI:
10.1016/j.celrep.2018.09.005
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