Angelman syndrome (AS) is a devastating neurological disorder in children characterized by severe mental retardation, absence of speech, tremor, ataxia, abnormal gait, inappropriate laughter, and seizures. AS is caused by maternal deletions of human chromosome 15q11-q13, paternal uniparental disomy (UPD) of chromosome 15, imprinting defects in 15q11-q13, or loss of function mutations in the ubiquitin-protein ligase (UBE3A) gene, which encodes the E6 associated protein (E6-AP). The AS gene (UBE3A) and the genes(s) responsible for Prader-Willi syndrome (PWS) reside in an imprinted PWS/AS domain that is highly conserved between mouse and human. Currently, little is known about the mechanisms regulating genomic imprintinting or the function of UBE3A in normal and AS affected individuals. Here, I propose to further expand the current knowledge of mechanisims regulating imprinting at Ube3a and the function of E6-AP by: 1) generating transgenic mice that facilitate the analysis of developmental and tissue specific expression of UbeSa, 2) determine the epigenetic modifications that modulate repression of the paternal UBeSa allele, and 3) determine the function(s) of the UBESA isoforms I, II, and III and their contributions to AS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD049248-01A1
Application #
7000228
Study Section
Special Emphasis Panel (ZRG1-F08 (20))
Program Officer
Oster-Granite, Mary Lou
Project Start
2006-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Dindot, Scott V; Antalffy, Barbara A; Bhattacharjee, Meenakshi B et al. (2008) The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 17:111-8