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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.

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Institute of Biochemistry, Kiel University, Kiel, Germany.
Institute of Psychology, Kiel University, Kiel, Germany.
Institute of Anatomy, Kiel University, Kiel, Germany.
CONARIS Research Institute AG, Kiel, Germany.
The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Institute of Biochemistry, Kiel University, Kiel, Germany. Electronic address:


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.


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

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