Analysis of genomic imprinting at the Ube3a locus.

Baylor College Of Medicine, Houston TX

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Abstract

DESCRIPTION (provided by applicant): 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.