The gamma-aminobutyric acid (GABAA) receptor alpha5, beta3 and gamma3 subunit genes are organized as a cluster in chromosome 15q11-q13. This chromosomal region contains the Angelman and Prader-Willi syndrome loci which are both subject to parental imprinting. This region also displays asynchronous DNA replication which is a characteristic of imprinted regions. A phage contig of the GABAA receptor cluster region, which spans more than 500kb of DNA, is nearly complete. It is proposed here to isolate additional genes from a 50-150kb subregion located between the beta3 and alpha5 subunit genes. In this subregion, DNA replication occurs at the beginning of S phase on the maternal chromosome but is delayed until the end of S on the paternal chromosome. The pattern of allele-specific replication within this relatively small domain is distinct from that of the flanking regions which display the opposite pattern with paternal before maternal replication. The genes isolated from the maternal early replicating domain will be characterized with respect to allele-specific expression and examined as potential candidate genes for the Angelman syndrome. A program of study is also proposed to identify DNA structures and modifications which are involved in establishing add/or maintaining the maternal early replication domain. The domain will be screened for sites of DNase l hypersensitivity, for scaffold attachment regions (SARs), and for allele-specific DNA methylation. All of these are important features of chromatin organization which could be crucial to the mechanism of parental imprinting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030628-06
Application #
2445788
Study Section
Special Emphasis Panel (ZRG2-MGN (Q1))
Program Officer
Spinella, Giovanna M
Project Start
1992-06-01
Project End
1998-08-31
Budget Start
1997-07-01
Budget End
1998-08-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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