Angelman syndrome (AS) is a genetic disease characterized by severe mental retardation, """"""""puppet-like"""""""" ataxic gait with jerky arm movements, hyperactivity and seizures. AS is caused by the absence of a normal maternal contribution to chromosome 15q11q13, a region that is subject to genomic imprinting. There are several molecular classes of AS including deletion, uniparental disomy and imprinting mutation. In addition, mutations have now been identified in a candidate AS gene, UBE3A. These findings indicate that AS not only results from the deletion or mutation of the imprinted UBE3A gene but also from a disregulation of the imprinting process. A better understanding of the function of imprinting and of how abnormal imprinting leads to loss of allele-specific transcription and DNA methylation is crucial to elucidating the molecular pathogenesis of AS and other imprinted genetic diseases. Three major areas of investigation related to this question are proposed here. The first is to study the tissue-specific imprinting of UBE3A by characterizing its promoter and studying its activity in different tissues where UBE3A is either imprinted or not. The UBE3A genomic region will also be searched for sites of allele-specific methylation and nuclease hypersensitivity. The second major area of proposed research involves the characterization of a duplication of the 5'-end of GABRA5 that has transposed to a locus proximal to the 15q11q13 region commonly deleted in PWS and AS. The duplicated region displays allelic methylation and is a recent evolutionary event. Further study of this locus may offer a unique opportunity to gain some insight into how allelic methylation is established. Finally, we will continue to investigate the mechanism of the homologous association of proximal 15q and its potential role in the regulation of imprinting in this region.
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