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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Oster-Granite, Mary Lou
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
Schools of Medicine
United States
Zip Code
Sacristán, Catarina; Schattgen, Stefan A; Berg, Leslie J et al. (2009) Characterization of a novel interaction between transcription factor TFII-I and the inducible tyrosine kinase in T cells. Eur J Immunol 39:2584-95
Ashworth, Todd; Roy, Ananda L (2009) Phase specific functions of the transcription factor TFII-I during cell cycle. Cell Cycle 8:596-605
Enkhmandakh, Badam; Makeyev, Aleksandr V; Erdenechimeg, Lkhamsuren et al. (2009) Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development. Proc Natl Acad Sci U S A 106:181-6
Tapia-Paez, Isabel; Tammimies, Kristiina; Massinen, Satu et al. (2008) The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia. FASEB J 22:3001-9
Roy, Ananda L (2007) Signal-induced functions of the transcription factor TFII-I. Biochim Biophys Acta 1769:613-21
Roy, Ananda L (2006) Transcription factor TFII-I conducts a cytoplasmic orchestra. ACS Chem Biol 1:619-22
Ku, Manching; Sokol, Sergei Y; Wu, Jack et al. (2005) Positive and negative regulation of the transforming growth factor beta/activin target gene goosecoid by the TFII-I family of transcription factors. Mol Cell Biol 25:7144-57