COMPARATIVE GENETICS OF SKELETAL DEFECTS

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DESCRIPTION (provided by applicant): The goal of this research is to understand the molecular mechanisms by which congenital skeletal disorders lead to pronounced developmental and radiological bone alterations. In particular the PIs are interested in two progressive hyperosteosis disorders: Van Buchem disease (VB) (MIM 239100) and Sclerosteosis (MIM 269500). VB is a severe, autosomal-recessive bone disorder characterized by cranio-facial distortion and generalized bone overgrowth. Sclerosteosis is a skeletal dysplasia highly similar to VB but with more pronounced radiological bone alterations (jaw; long bones; gigantism) and the presence of hand abnormalities (syndactyly). Linkage analysis mapped both diseases to the same locus (17q12-q21), and Sclerosteosis patients were found to carry several coding mutations in the BMP-antagonist gene Sclerostin (Sost). In contrast, VB patients exhibit no Sost coding mutations, however displayed a 52kb noncoding deletion, 35kb downstream of the Sost transcript. Using human transgenes in mice, the PIs have demonstrated that sclerosteosis and VB are allelic, and that the 52kb deletion removes essential Sost transcriptional regulatory elements, altering the human Sost expression pattern. Also, in mice, increased levels of Sost result in severe limb abnormalities (fused and split digits), while the lack of mouse Sost leads to hyperosteosis. These initial observations suggest that Sost plays a critical role during limb development as well as throughout the adult-life controlling bone homeostasis in vertebrates. Since Sost is highly conserved from fishes to humans, the PIs are interested in elucidating the role of this molecule during skeletal development in different vertebrates. Accordingly, this grant focuses on deciphering several fundamental properties of Sost including 1) identification and characterization of Sost-specific regulatory elements, 2) determination of the role of Sost in limb patterning and adult bone homeostasis, and 3) investigation of the role of Sost across different vertebrate lineages.