Maternally derived duplications or triplications of 15q11.2-q13 (Dup15q) are one of the most common genetic variations associated with autism spectrum disorder (ASD), detected in 1-3% of cases. Prominent features commonly found in Dup15q include intellectual disability (ID), epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. The ubiquitin E3A ligase gene (UBE3A), which maps to the 15q11.2-q13 region, has been implicated in multiple neurodevelopmental disorders, including ASD, Angelman Syndrome (AS), Prader-Willi Syndrome (PWS) and ID. Based on this information, we postulate that dysregulated UBE3A has deleterious outcomes. Because UBE3A is imprinted specifically in neurons, we will use novel mouse models to test the hypothesis that elevated UBE3A in neurons is the major contributor to phenotypes. It is well known that three differentially spliced isoforms of UBE3A exist, propelling us to pursue the secondary scientific question of which isoform plays the most critical role in Dup15q. No in vivo studies, to date, have evaluated the phenotypic contributions associated with each of the three Ube3a isoforms. Preliminary data illustrate our discovery that forebrain, neuronal selective overexpression of Ube3a isoform 2 is sufficient to cause behavioral and anatomical phenotypes. Here, we propose a multifaceted, collaborative project to identify behavior, neuroanatomical and epigenetic mechanisms of isoform-specific Ube3a overexpression. This proposal will directly address the most important questions regarding our main scientific premise that overexpression of UBE3A is the principal pathogenic mechanism causing Dup15q impairments. We will also address our secondary premise, that different Ube3a isoforms in neurons cause differential behavioral, pathological and epigenetic anomalies. We will delineate phenotypes and identify pathologies in each line of isoform-specific Ube3a- overexpressing mice. Significant correlations and corroborations between molecular, cellular, histopathological and behavioral phenotypes will reveal key information on neural substrates of Dup15q phenotypes. These studies will answer the most important questions regarding the pathogenic nature of mechanisms underlying UBE3A overexpression.
Duplications or triplications of the chromosomal region 15q11.2-q13 (Dup15q) are one of the most common genetic causes of autism and intellectual disability. The ubiquitin E3A ligase gene (UBE3A) located within the 15q11.2-q13 region is parentally imprinted and expressed only from the maternal allele in most neurons. Three differentially spliced isoforms of UBE3A have been identified; however, it is not known which isoform plays the most critical role in Dup15q. Since UBE3A is imprinted specifically in neurons, this project will test the hypothesis that elevated UBE3A in neurons is the major contributor to Dup15q phenotypes. We will further assess to the contribution of each isoform of Ube3a, by characterizing functional outcomes, neuropathology, and epigenetic marks in transgenic mice with neuronal forebrain overexpression of Ube3a Isoform 1, 2, and 3.
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| Copping, Nycole A; Christian, Sarah G B; Ritter, Dylan J et al. (2017) Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome. Hum Mol Genet 26:3995-4010 |
