Abstract
ABSTRACTNovel 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 (PGWAS = 6 × 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 hypothesize 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. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Highlights
Age-related bone loss with deterioration of skeletal architecture leads to osteoporosis, affecting 8.2 million women and 2.0 million men aged 50 years and older in the United States (US) [1]
high bone mass (HBM) pedigree with a segregating SMAD9 c.65T>C p.Leu22Pro variant (Fig 1 and Table 1) We investigated a pedigree with unexplained and apparently autosomal dominant HBM [9], identified from our large UK HBM cohort [10] (Fig. 1)
Rs12427846 [the lead SNP from these estimated BMD (eBMD) results] is associated with DXA-measured total body BMD [45] and fracture risk [17], consistent with associations with BMD identified in our PheWAS. These findings provide further evidence of the importance of SMAD9 in bone biology and are equivalent to reported associations for common variants annotated to LRP5 and SOST genes, both implicated in monogenic HBM disorders [46, 47]
Summary
Age-related bone loss with deterioration of skeletal architecture leads to osteoporosis, affecting 8.2 million women and 2.0 million men aged 50 years and older in the United States (US) [1]. Gain-of-function mutations in LRP5 and LRP6 can cause extreme HBM [7, 8] Together these sclerosing bone dysplasias are characterised by mandible enlargement with tori of the palate and mandible, bone overgrowth leading to nerve compression, a tendency to sink when swimming, and, importantly, resistance to fracture [5, 7, 9]. These important gene discoveries validate the study of rare monogenic HBM as an approach to identify novel therapeutic targets for drug development towards osteoporosis treatments
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