ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2016
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.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 34 citations in OpenAlex.
- Review
- Humeroradial Synostosis: An Updated Classification and Differential Diagnosis Based on Genetic Aetiology.Clinical genetics · 2025Review
- The master male sex determinant Gdf6Y of the turquoise killifish arose through allelic neofunctionalization.Nature communications · 2025Article
- Timing and Graded BMP Signalling Determines Fate of Neural Crest and Ectodermal Placode Derivatives from Pluripotent Stem Cells.Biomedicines · 2024Review
- Transforming growth factor beta signaling and craniofacial development: modeling human diseases in zebrafish.Frontiers in cell and developmental biology · 2024Review
- Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life.Kidney international reports · 2023Article
- Complex clinical manifestations and new insights in RNA sequencing of children with diabetes andFrontiers in endocrinology · 2023Article
- Clinical observation and genetic analysis of a SYNS1 family caused by novel NOG gene mutation.Molecular genetics & genomic medicine · 2022Article
- Identification and functional analysis of novelFrontiers in genetics · 2022Article
- Article
- Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia.Journal of diabetes investigation · 2021Article
- Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development.The Journal of clinical investigation · 2020Article
- Extracellular Vesicles Derived from Human Gingival Mesenchymal Stem Cells: A Transcriptomic Analysis.Genes · 2020Article
- Circulating noggin levels following treatment with denosumab or teriparatide in postmenopausal women with low bone mass.Journal of musculoskeletal & neuronal interactions · 2019Observational
- A NovelMolecular syndromology · 2019Article
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Authors and funding
17 authors at 5 institutions in 4 countries.
Funding
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.
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