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 x 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.<\/p>\n","protected":false},"excerpt":{"rendered":"
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