With the Human Genome Project promising to provide a catalog of all human genes in the near future, the main challenge of research in the next century is that of functional genomics. The processes that control gene activation and repression in a developmental-stage and cell-type specific manner are fundamental to understanding normal development and discovering the causes of human disease. Spontaneously recurring microdeletions are ideal for a systematic study of the downstream effects of hemizygosity for the defined set of genes in the deletion. Williams-Beuren syndrome (WBS), a neurodevelopmental disorder with a distinct profile of cognitive and behavioral features serves as a model system to study the genetic and molecular basis of cognition, speech, language, and visuo-spatial processing. WBS is caused by recurrent uniform deletions of 1.6 Mb of DNA from chromosome 7q11.23, that arise by inter- or intrachromosomal recombination between flanking duplicated regions. Within the deletion, 16 genes have been identified and characterized. They function as transcription factors, in DNA replication, chromatin assembly, translation, signal transduction and as structural proteins. Only one, the elastin gene has been linked to a specific manifestation, supravalvular aortic stenosis. To evaluate the functional consequences of hemizygosity for the other genes, humans with partial deletions will be identified and mouse models generated with corresponding deletions in the conserved syntenic region on mouse chromosome 5. Target genes of transcription factors and signaling molecules will be identified by microarray studies, comparing gene expression patterns in various tissues from affected humans and deletion mice. Development of a molecular phenotype of WBS links cognitive neuroscience to molecular genetics. Insights gained into the molecular pathways, that lead from the chromosomal deletion to the specific cognitive, behavioral and learning disabilities may have relevance for common developmental disorders, such as attention deficit/hyperactivity disorder and autism, as well as for understanding normal developmental processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039927-03
Application #
6637998
Study Section
Genome Study Section (GNM)
Program Officer
Oster-Granite, Mary Lou
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$438,175
Indirect Cost
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Goergen, Craig J; Li, Hong-Hua; Francke, Uta et al. (2011) Induced chromosome deletion in a Williams-Beuren syndrome mouse model causes cardiovascular abnormalities. J Vasc Res 48:119-29
Li, Hong Hua; Roy, Madhuri; Kuscuoglu, Unsal et al. (2009) Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med 1:50-65