MOLECULAR ANALYSIS OF WILLIAMS SYNDROME

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DESCRIPTION (provided by applicant): Williams-Beuren Syndrome (WBS) is a neuro-developmental disorder with multisystem manifestations, including supravalvar aortic stenosis (SVAS), hypercalcemia in infancy, mild to moderate mental retardation, cognitive defects and characteristic craniofacial features. The frequency of this genetic haploinsufficiency is estimated to be 1 in 20,000 live births. WBS is caused by a hemizygous microdeletion of approximately 1.5 MB, spanning 17 genes at chromosomal location 7q11.23. Despite these observations, we lack a complete understanding of molecular basis for this disorder. Although this multisystem dysfunction with unusual craniofacial, behavioral and cognitive features occurs most likely due to haplo-insufficiency of several genes, rare cases with much smaller deletions have provided clues to identifying specific genes that may be causal to distinctive physical and cognitive defects. Two of these genes, GTF21 and GTF3 encode the TFII-I family of transcription factors. TFII-I and its relative MusTRD1/BEN exhibit extensive and overlapping expression patterns in a variety of tissues during mouse pre- and post-implantation development, suggesting a functional role for these proteins in early development. These proteins are also abundantly expressed in the hippocampus, a portion of the brain that plays a role in learning and memory, further indicating that they may be causal to some WBS traits. While much has been learned about the TFII-I's mechanism of action, relatively little is known about how MusTRD1/BEN functions. To better understand the molecular basis for WBS, we propose to dissect the functional role of MusTRD1/BEN. We will proceed to analyze the physical and functional interactions of MusTRD1/BEN with Smad factors, which are critical for a variety of developmental processes. Finally, we will employ RNAi technologies to determine the biological role of this factor in osteoblast differentiation.