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- Title
A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal.
- Authors
Jian Wang; Tingting Yu; Zhigang Wang; Satoshi Ohte; Ru-en Yao; Zhaojing Zheng; Juan Geng; Haiqing Cai; Yihua Ge; Yuchan Li; Yunlan Xu; Qinghua Zhang; Gusella, James F.; Qihua Fu; Pregizer, Steven; Rosen, Vicki; Yiping Shen
- Abstract
Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP-001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild-type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development.
- Subjects
CRANIOSYNOSTOSES; MOLECULAR physics; COCHLEAR implants; MORPHOLOGY; COMPARATIVE anatomy
- Publication
Journal of Bone & Mineral Research, 2016, Vol 31, Issue 4, p882
- ISSN
0884-0431
- Publication type
Article
- DOI
10.1002/jbmr.2761