A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis.

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 domai

SUBMITTER: Gregson CL 

PROVIDER: S-EPMC7004081 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature