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.
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.
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohte
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Ru-En
authors.initials: RE
authors.lastname: Yao
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yuchan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Pregizer
authors.affiliation: Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Rosen
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.|Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA.|Claritas Genomics, Cambridge, MA, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002348:Carpal Bones / Q000002:abnormalities* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000378:metabolism; D055431:Growth Differentiation Factor 6 / Q000235:genetics / Q000378:metabolism; D006228:Hand Deformities, Congenital / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D015398:Signal Transduction / Q000235:genetics*; D013199:Stapes / Q000002:abnormalities* / Q000378:metabolism; D013580:Synostosis / Q000235:genetics / Q000378:metabolism; D013639:Tarsal Bones / Q000002:abnormalities* / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D055431:Growth Differentiation Factor 6; D000099176:Noggin Protein; C525906:GDF6 protein, human
keywords: BMP/TGF-β SIGNALING; GDF6; MULTIPLE SYNOSTOSES SYNDROME; NOG