This maternal imprinting defect results in expression of maternal Ube3a-as and repression of Ube3a in cis, providing evidence that Ube3a is regulated by its antisense and creating the first reported mouse model for AS imprinting defects.
Using a quantitative PCR assay, we have found that the ratio of SNURF-SNRPN/UBE3A transcript levels is increased in blood cells of AS patients with an imprinting defect, but not in AS patients with a UBE3A mutation or an unknown defect.
The E6AP ubiquitin-protein ligase (E3) mediates the human papillomavirus-induced degradation of the p53 tumor suppressor in cervical cancer and is mutated in Angelman syndrome, a neurological disorder.
As compared to training with massed trials, spaced training significantly improved learning in both the Ts65Dn trisomy mouse model of Down syndrome and the maternally inherited Ube3a mutant mouse model of Angelman syndrome.
Loss of E6AP expression leads to the development of Angelman syndrome (AS), clinically characterized by lack of speech, abnormal motor development, and the presence of seizures.
UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood.
In this study, we performed a genome-wide microarray analysis on the maternal Ube3a-deficient (Ube3a(m-/p+)) AS mouse to search for genes affected in the absence of Ube3a.
Other genetic mechanisms such as paternal uniparental disomy, imprinting defect and mutation in the UBE3A gene are present in smaller groups of patients with AS.
The second family is a mother and son both of whom have mental retardation but no other features of Angelman syndrome despite an extensive DNA deletion on the telomeric side of UBE3A.
The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities.
This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS.
Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype.
While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood.
Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in <i>Ube3a</i><sup><i>m</i>-/<i>p</i>+</sup> mice, which may underlie the cognitive deficits observed in AS.
Thus, our results identify HAP1 as an in vivo UBE3A target that contributes to deregulated autophagy and synaptic dysfunction in the central nervous system of AS mouse.