ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2020
A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- New insights into bone pathology through a transcriptomic profiling of an osteoblast model of Gaucher disease.Molecular genetics and metabolism reports · 2026Article
- The pathogenesis and intersecting mechanisms of monogenic bone mass disorders.Nature reviews. Endocrinology · 2026Review
- Mandibular Cortical Thickness Predicts Skull BMD in Adolescents.Calcified tissue international · 2026Article
- TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease.Bone research · 2026Review
- Article
- The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease.Cell research · 2024Review
- Longevity-Associated Transcription Factor ATF7 Promotes Healthspan by Suppressing Cellular Senescence and Systematic Inflammation.Aging and disease · 2023Article
- Genome-wide association study identified six loci associated with adverse drug reactions to aripiprazole in schizophrenia patients.Schizophrenia (Heidelberg, Germany) · 2023Article
- Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Review
- Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci.JBMR plus · 2022Article
- Evaluating Osteogenic Differentiation of Osteoblastic Precursors Upon Intermittent Administration of PTH/IGFBP7.Frontiers in pharmacology · 2022Article
- Genome-wide family-based study in torus palatinus affected individuals.Archives of oral biology · 2021Article
- Astragaloside IV inhibits adriamycin-induced cardiac ferroptosis by enhancing Nrf2 signaling.Molecular and cellular biochemistry · 2021Article
- Osteoarthritis: Insights Offered by the Study of Bone Mass Genetics.Current osteoporosis reports · 2021Review
- Pharmacological Manipulation of Early Zebrafish Skeletal Development Shows an Important Role for Smad9 in Control of Skeletal Progenitor Populations.Biomolecules · 2021Article
- Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study.Arthritis research & therapy · 2021Article
- A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders.Frontiers in endocrinology · 2021Review
- Fish Models of Induced Osteoporosis.Frontiers in cell and developmental biology · 2021Review
- Fibrodysplasia ossificans progressiva: current concepts from bench to bedside.Disease models & mechanisms · 2020Review
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 2 countries.
Funding
Abstract
Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (P
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Registered trials
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