A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target
Celia L Gregson,
Richard B. Sessions,
April E Hartley,
Peter I Croucher,
Aideen M McInerney-Leo,
Jonathan CY Tang,
George Davey Smith,
The AOGC Consortium,
Matthew A Brown,
Chrissy L Hammond,
John P Kemp,
Jon H Tobias,
Emma L Duncan
Posted 25 Feb 2019
bioRxiv DOI: 10.1101/560565
Posted 25 Feb 2019
To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals 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, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in >362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6x10-16; PGENE =8x10-17). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.
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