Angelman Syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. AS is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of the 15q11-q13 chromosome inherited from the mother, including: a deletion of the region q11.2-q13 on the maternally inherited chromosome 15;a mutation in the UBE3A gene;paternal uniparental disomy in which the father contributes both copies of chromosome 15;an imprinting defect;or through an as yet unidentified mechanism. Work in our laboratory has centered upon identifying a molecular basis for the disease that lies downstream of UBE3A maternal deficiency. We recently demonstrated that genetic ablation of the auto-inhibitory site of 1CaMKII can rescue the major phenotypes of the Ube3a m-/p+ mouse. These results suggest that the major site of biochemical dysfunction in the AS mouse model is down- stream of CaMKII. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. We present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3a m-/p+ mouse model. We have developed three distinct therapeutic interventions to determine if the Ube3a m-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Our goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment and identify the optimal molecular targets for future human therapeutic research.
Angelman Syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 populations. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.
|Daily, Jennifer; Smith, Amanda G; Weeber, Edwin J (2012) Spatial and temporal silencing of the human maternal UBE3A gene. Eur J Paediatr Neurol 16:587-91|