Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology

项目总结

PROJECT SUMMARY Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A, although other genes in the region are also deleted. AS can also result from loss of function mutations of UBE3A, which spares the other genes located in the region. UBE3A mutation AS patients typically have a milder phenotype, especially with regard to epilepsy and seizures. This suggests that the loss of other genes in the region, in addition to UBE3A, likely contribute to the severe epilepsy phenotype in deletion AS patients. In particular, a cluster of genes encoding three GABAA receptor subunits is located within the region typically deleted in AS. Reduced expression of these subunits has been implicated in several human neurodevelopmental disorders such as Angelman syndrome, certain syndromic forms of epilepsy, and autism. We hypothesize that hemizygous loss of GABRB3, GABRA5, and/or GABRG3, in conjunction with loss of UBE3A expression, causes neuronal hyperexcitability and enhanced seizure susceptibility in human AS individuals. We will test this hypothesis by comparing the physiological phenotype of AS neurons derived from mutation and deletion AS patients. We will use antisense oligonucleotide approaches to determine if knocking down expression of these GABA receptor subunits in a UBE3A deficient line will confer the increased excitability seen in neurons derived from AS deletion patients. These studies will shed light on the cellular mechanisms responsible for seizures in AS and identify targets for development of novel therapeutics.