scholarly journals Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion

2020 ◽  
Vol 13 (3) ◽  
pp. 397-409 ◽  
Author(s):  
Andie Dodge ◽  
Melinda M. Peters ◽  
Hayden E. Greene ◽  
Clifton Dietrick ◽  
Robert Botelho ◽  
...  
Keyword(s):  
Rat Model ◽  
Angelman Syndrome ◽  
Gene Deletion ◽  
Ube3a Gene

scholarly journals Early developmental EEG and seizure phenotypes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

eNeuro ◽  
2021 ◽  
pp. ENEURO.0345-20.2020
Author(s):  
Heather A. Born ◽  
Luis A. Martinez ◽  
Amber T. Levine ◽  
Sarah E. Harris ◽  
Shubhangi Mehra ◽  
...  
Keyword(s):  
Rat Model ◽  
Angelman Syndrome ◽  
Gene Deletion ◽  
Ubiquitin Protein Ligase ◽  
Early Developmental

scholarly journals Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
E. L. Berg ◽  
M. C. Pride ◽  
S. P. Petkova ◽  
R. D. Lee ◽  
N. A. Copping ◽  
...  
Keyword(s):  
Rat Model ◽  
Angelman Syndrome ◽  
Gene Deletion ◽  
Ubiquitin Protein Ligase

scholarly journals Angelman Syndrome: An Autism Spectrum Disorder

2018 ◽  
Vol 6 (2) ◽  
pp. 56-60
Author(s):  
Andrew J. Kennedy ◽  
Jeffrey O. Henderson
Keyword(s):  
Angelman Syndrome ◽  
Motor Development ◽  
Neurodevelopmental Disorders ◽  
Muscle Tension ◽  
Autism Spectrum ◽  
Speech Impairment ◽  
Social Lives ◽  
Genetic Abnormalities ◽  
Ube3a Gene ◽  
Genetic Mechanisms

Neurodevelopmental disorders limit the mental, physical, and social lives of affected individuals and their families. These disorders are often related to genetic abnormalities having a distinct chromosomal location. The abnormalities can cause incorrect proteins to be formed or biochemical pathways to be blocked, predominately affecting brain development, but also having pleiotropic effects. Research into defining and correcting these genetic abnormalities is important to help distinguish between unique neurodevelopmental disorders so that proper clinical interventions are available for affected individuals. In the following review, Angelman syndrome, which results from UBE3A gene function being lost at maternal chromosome  15q11.2-q13, will be discussed. Angelman patients suffer from the defining characteristics of speech impairment, uncontrolled laughing and smiling, motor development issues, muscle tension, and possible ataxia. The genetic mechanisms of the disorder as well as possible therapies will be discussed, with future areas of research into genetic therapies to treat Angelman syndrome also put forth. Research into Angelman syndrome can provide an avenue for a clearer understanding of other neurodevelopmental disorders.

scholarly journals Novel Insights into the Role of UBE3A in Regulating Apoptosis and Proliferation

2020 ◽  
Vol 9 (5) ◽  
pp. 1573 ◽  
Author(s):  
Lilach Simchi ◽  
Julia Panov ◽  
Olla Morsy ◽  
Yonatan Feuermann ◽  
Hanoch Kaphzan
Keyword(s):  
Angelman Syndrome ◽  
Critical Role ◽  
Embryonic Fibroblasts ◽  
Ubiquitin E3 Ligase ◽  
Proliferation And Apoptosis ◽  
Ube3a Gene ◽  
Ubiquitin Binding ◽  
Molecular Effects ◽  
Substrate Proteins

The UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression leads to Angelman syndrome (AS), while its overexpression is associated with autism. In spite of extensive research, our understanding of UBE3A roles is still limited. We investigated the cellular and molecular effects of Ube3a deletion in mouse embryonic fibroblasts (MEFs) and Angelman syndrome (AS) mouse model hippocampi. Cell cultures of MEFs exhibited enhanced proliferation together with reduced apoptosis when Ube3a was deleted. These findings were supported by transcriptome and proteome analyses. Furthermore, transcriptome analyses revealed alterations in mitochondria-related genes. Moreover, an analysis of adult AS model mice hippocampi also found alterations in the expression of apoptosis- and proliferation-associated genes. Our findings emphasize the role UBE3A plays in regulating proliferation and apoptosis and sheds light into the possible effects UBE3A has on mitochondrial involvement in governing this balance.

scholarly journals Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways

2019 ◽  
Author(s):  
S. Jesse Lopez ◽  
Benjamin I. Laufer ◽  
Ulrika Beitnere ◽  
Elizabeth L. Berg ◽  
Jill L. Silverman ◽  
...  
Keyword(s):  
Systems Biology ◽  
Wnt Signaling ◽  
Mouse Models ◽  
Rat Model ◽  
Angelman Syndrome ◽  
Gene Networks ◽  
Neurodevelopmental Disorder ◽  
Postnatal Brain ◽  
Parent Of Origin ◽  
The Brain

AbstractThe genomically imprinted UBE3A gene encodes a E3 ubiquitin ligase whose loss from the maternal allele leads to the neurodevelopmental disorder Angelman syndrome. However, the mechanisms by which loss of maternal UBE3A contribute to severe neurodevelopmental phenotypes are poorly understood. Previous studies of UBE3A function have focused on mouse models or single targets, but these approaches do not accurately reflect the complexity of imprinted gene networks in the brain nor the systems-level cognitive dysfunctions in Angelman syndrome. We therefore utilized a systems biology approach to better elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9 engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring derived from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, when compared to wild-type sex-matched littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype, and time (P2, P9) was investigated through transcriptome (RNA-seq of cortex and hypothalamus) and methylome (whole genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring correlated with postnatal age that were enriched in developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment, and splicing. Furthermore, using this novel rat model, we showed that loss of the paternally expressed Ube3a antisense transcript resulted inboth unique and overlapping dysregulated gene pathways, predominantly at the level of differential methylation, when compared to loss of maternal Ube3a. Together, these results provide the most holistic examination to date of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.Author SummaryThe neurodevelopmental disorder Angelman syndrome is caused by loss of UBE3A from the maternal chromosome. UBE3A is a genomically imprinted gene, which results in parent-of-origin specific expression of a protein from the mother and a noncoding RNA from the father. While mouse models have been useful in investigating diverse roles for UBE3A, their partial mutations are of limited utility for investigating parental imprinting effects or identifying a complete list of downstream differences in gene pathways relevant to developing therapies for Angelman syndrome. To address this limitation, we utilized a novel rat model with a CRISPR/Cas9 engineered full UBE3A deletion and systems biology approaches to better understand how UBE3A loss affects early postnatal brain development. We discovered that UBE3A loss has widespread effects on many important neuronal and cellular pathways and uncovered interesting interactions between maternal and paternal genes that were not previously considered. Taken together, our findings provide the most comprehensive view of UBE3A’s influences in the brain, which are relevant to the understanding and development of treatments for Angelman syndrome and related neurodevelopmental disorders.

Screening of UBE3A gene in patients referred for Angelman Syndrome

2013 ◽  
Vol 17 (4) ◽  
pp. 366-373 ◽  
Author(s):  
Evmorfia Tzagkaraki ◽  
Christalena Sofocleous ◽  
Fryssira-Kanioura Helen ◽  
Argyris Dinopoulos ◽  
Georgios Goulielmos ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Ube3a Gene

Angelman Syndrome Due to a Novel Splicing Mutation of the UBE3A Gene

2008 ◽  
Vol 23 (8) ◽  
pp. 912-915 ◽  
Author(s):  
Stefano Sartori ◽  
Laura Anesi ◽  
Roberta Polli ◽  
Irene Toldo ◽  
Alberto Casarin ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Splicing Mutation ◽  
Ube3a Gene

scholarly journals Novel intragenic deletions within the UBE3A gene in two unrelated patients with Angelman syndrome: case report and review of the literature

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Cinthia Aguilera ◽  
Marina Viñas-Jornet ◽  
Neus Baena ◽  
Elisabeth Gabau ◽  
Concepción Fernández ◽  
...  
Keyword(s):  
Case Report ◽  
Angelman Syndrome ◽  
Review Of The Literature ◽  
Ube3a Gene ◽  
Intragenic Deletions
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