The observed differences in sex-dependent neurobehavioral phenotypes and the differential transcriptome expression profiles in AS mice strengthen the evidence for molecular cross talk between Ube3a protein and sex hormone receptors or their elicited pathways.
Taken together, our findings elucidate the mechanisms underlying the subcellular localization of UBE3A, and indicate that the nuclear UBE3A isoform is the most critical for the pathophysiology of Angelman syndrome.
Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome.
However, such efforts have yielded less-than-expected rescue effects in AS mouse models, raising the concern that activation of paternal UBE3A after a critical period cannot correct all the CNS defects that developed in a UBE3A-deficient environment.
Screening for mutations in this gene should be considered in patients who present with findings of AS but who have been negative for methylation and UBE3A testing.
Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.
In the current study, we demonstrate a profound structural disruption and cisternal swelling of the Golgi apparatus (GA) in the cortex of AS (UBE3A(m-/p+)) mice.
The study highlights the phenotypic overlap between autism and AS and increases the probability that dysregulation of UBE3A may play a role in the causation of autism.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy, imprinting defect, or UBE3A mutation.
We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings.
We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication.
The neuronal and molecular mechanisms underlying mouse fluid consumption defects specifically associated with maternally inherited Ube3a deficiency may reveal important new insights into the pathobiology of AS in humans.
The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice.
These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.
We established human induced pluripotent stem cells (iPSCs) from an Angelman syndrome patient with the deletion of maternal 15q11.2-q13 including UBE3A gene.
In chromosomal structure analyses, we found four de novo CNVs and one de novo chromosomal rearrangement event, including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to de novo chromosomal translocation t(1; 5)(q25.1; q33.2).
Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited UBE3A allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect.
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally-inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS) at the unmethylated paternal locus.