Deletions of the proximal long arm of chromosome 15 are found in the majority of patients with two distinct genetic disorders, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). The deletions in the two syndromes, defined cytogenetically and molecularly, are similar in extent but differ in parental origin. Deletions in AS occur on the maternally-inherited chromosome, whereas deletions in PWS are exclusively of paternal origin. In several nondeletion cases of PWS, uniparental maternal disomy has been detected. Uniparental paternal disomy has now been observed in nondeletion AS cases. These findings strongly suggest that one or more genes in this region are subject to genomic imprinting. The gene encoding the GABAA (tau-aminobutyric acid) receptor beta3 subunit has been localized to the AS/PWS subregion. Additional mapping data indicate that the GABAA receptor beta3 subunit gene can be excluded from the critical region of deletion overlap of PWS but not that of AS. Functionally, a defect in a receptor for tau-aminobutyric acid, which is the principal inhibitory neurotransmitter in vertebrate brain, could account for the clinical manifestations of AS which include seizures, jerky arm movements, severe mental retardation and uncontrollable bouts of laughter. In order to investigate whether an abnormality in this neurotransmitter receptor is associated with the development of AS, the DNA of nondeletion AS patients will be screened for mutations and rearrangements of this gene. Antibodies to the GABAA receptor beta3 subunit will be raised in order to investigate its expression in normal and AS brain. The other main objective of this proposal is to investigate whether the GABAA receptor beta3 subunit gene is imprinted. Among the approaches that will be used to address the latter goal is the study of the methylation pattern of the beta3 subunit gene on the paternally- and maternally-derived chromosomes 15, and the investigation of whether the paternal and maternal beta3 subunit alleles are differentially expressed in mouse brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030628-03
Application #
2268602
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-06-01
Project End
1995-07-31
Budget Start
1994-06-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
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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