Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.

ABSTRACT: Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization w

SUBMITTER: Kang H 

PROVIDER: S-EPMC7201932 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature