RGD Reference Report - Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. - Rat Genome Database

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Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model.

Authors: Silva-Santos, Sara  van Woerden, Geeske M  Bruinsma, Caroline F  Mientjes, Edwin  Jolfaei, Mehrnoush Aghadavoud  Distel, Ben  Kushner, Steven A  Elgersma, Ype 
Citation: Silva-Santos S, etal., J Clin Invest. 2015 May;125(5):2069-76. doi: 10.1172/JCI80554. Epub 2015 Apr 13.
RGD ID: 12859273
Pubmed: PMID:25866966   (View Abstract at PubMed)
PMCID: PMC4463212   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI80554   (Journal Full-text)

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Angelman syndrome treatmentISOUbe3a (Mus musculus)12859273; 12859273 RGD 
Angelman syndrome treatmentIMP 12859273 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ube3a  (ubiquitin protein ligase E3A)

Genes (Mus musculus)
Ube3a  (ubiquitin protein ligase E3A)

Genes (Homo sapiens)
UBE3A  (ubiquitin protein ligase E3A)


Additional Information