A rare mutation in SMAD9 associated with high bone mass identifies the SMAD-dependent BMP signalling pathway as a potential anabolic target for osteoporosis

Matthew A Brown, Christina Hammond, John P Kemp, Emma L Duncan, AOGC Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 modelling 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 computer 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 seen. 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 (PGWAS = 6 x 10‐16; PGENE = 8 × 10‐17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP) dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesise SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation.
Original languageEnglish
Pages (from-to)92-105
Number of pages40
JournalJournal of Bone and Mineral Research
Issue number1
Early online date16 Sept 2019
Publication statusPublished - 1 Jan 2020


  • High Bone Mass
  • SMAD9
  • DXA
  • exon sequencing
  • monogenic
  • zebrafish
  • osteoanabolic


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