Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice.
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.
['Agthe|Maria|M|', 'Brügge|Julian|J|', 'Garbers|Yvonne|Y|', 'Wandel|Marieke|M|', 'Kespohl|Birte|B|', 'Arnold|Philipp|P|', 'Flynn|Charlotte M|CM|', 'Lokau|Juliane|J|', 'Aparicio-Siegmund|Samadhi|S|', 'Bretscher|Christian|C|', 'Rose-John|Stefan|S|', 'Waetzig|Georg H|GH|', 'Putoczki|Tracy|T|', 'Grötzinger|Joachim|J|', 'Garbers|Christoph|C|']
D000595:Amino Acid Sequence D000818:Animals D003398:Craniosynostoses D004195:Disease Models, Animal D004721:Endoplasmic Reticulum D005260:Female D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D017370:Interleukin-11 D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008958:Models, Molecular D009154:Mutation D053702:Receptors, Interleukin-11 D015398:Signal Transduction
craniosynostosis interleukin-11 development endoplasmic reticulum trans-signaling gp130 interleukin-6 osteoclast