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Sarah F Pollack, Olivia R Grocott, Kimberly A Parkin, Anna M Larson, Ronald L Thibert
Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS...
March 16, 2018: Epilepsy & Behavior: E&B
Jana Stanurova, Anika Neureiter, Michaela Hiber, Hannah de Oliveira Kessler, Kristin Stolp, Roman Goetzke, Diana Klein, Agnes Bankfalvi, Hannes Klump, Laura Steenpass
This corrects the article DOI: 10.1038/srep30792.
March 8, 2018: Scientific Reports
Isabel Saez, Seda Koyuncu, Ricardo Gutierrez-Garcia, Christoph Dieterich, David Vilchez
Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts...
March 6, 2018: Scientific Reports
Michael S Sidorov, Matthew C Judson, Hyojin Kim, Marie Rougie, Alejandra I Ferrer, Viktoriya D Nikolova, Natallia V Riddick, Sheryl S Moy, Benjamin D Philpot
Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Gustavo Martínez-Noël, Katja Luck, Simone Kühnle, Alice Desbuleux, Patricia Szajner, Jeffrey T Galligan, Diana Rodriguez, Leon Zheng, Kathleen Boyland, Flavian Leclere, Quan Zhong, David E Hill, Marc Vidal, Peter M Howley
Perturbations in activity and dosage of the UBE3A ubiquitin-ligase have been linked to Angelman Syndrome and autism spectrum disorders. UBE3A was initially identified as the cellular protein hijacked by the human papillomavirus E6 protein to mediate the ubiquitylation of p53, a function critical to the oncogenic potential of these viruses. Although a number of substrates have been identified, the normal cellular functions and pathways affected by UBE3A are largely unknown. Previously we showed that UBE3A associates with HERC2, NEURL4, and MAPK6/ERK3 in a high molecular weight complex of unknown function that we refer to as the HUN complex (HERC2, UBE3A, and NEURL4)...
February 6, 2018: Journal of Molecular Biology
Nora Urraca, Kevin Hope, A Kaitlyn Victor, T Grant Belgard, Rawaha Memon, Sarita Goorha, Colleen Valdez, Quynh T Tran, Silvia Sanchez, Juanma Ramirez, Martin Donaldson, Dave Bridges, Lawrence T Reiter
Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls...
2018: Molecular Autism
Wangfang Ping, Jian Hu, Gongcheng Hu, Yawei Song, Qing Xia, Mingze Yao, Shixin Gong, Cizhong Jiang, Hongjie Yao
Induced pluripotent stem cells can be derived from somatic cells through ectopic expression of transcription factors or chemical cocktails. Chemical iPSCs (C-iPSCs) and OSKM-iPSCs (4F-iPSCs) have been suggested to have similar characteristics to mouse embryonic stem cells (mESCs). However, their epigenetic equivalence remains incompletely understood throughout the genome. In this study, we have generated mouse C-iPSCs and 4F-iPSCs, and further compared the genome-wide DNA methylomes of C-iPSCs, 4F-iPSCs, and mESCs that were maintained in 2i and LIF...
February 7, 2018: Cell Death & Disease
Jimmy El Hokayem, Edwin Weeber, Zafar Nawaz
Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2-15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A, which is located in this region, and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e...
January 31, 2018: Molecular Neurobiology
Nicole Brimer, Camille M Drews, Scott B Vande Pol
Papillomavirus E6 proteins bind to LXXLL peptide motifs displayed on targeted cellular proteins. Alpha genus HPV E6 proteins associate with the cellular ubiquitin ligase E6AP (UBE3A), by binding to an LXXLL peptide (ELTLQELLGEE) displayed by E6AP, thereby stimulating E6AP ubiquitin ligase activity. Beta, Gamma, and Delta genera E6 proteins bind a similar LXXLL peptide (WMSDLDDLLGS) on the cellular transcriptional co-activator MAML1 and thereby repress Notch signaling. We expressed 45 different animal and human E6 proteins from diverse papillomavirus genera to ascertain the overall preference of E6 proteins for E6AP or MAML1...
December 27, 2017: PLoS Pathogens
Jyotindra Narayan Goswami, Jitendra Kumar Sahu, Pratibha Singhi
A 12-y-old boy presented with developmental delay, autism, epilepsy, limb tremors and behavioral problems which posed a diagnostic challenge. Though his clinical profile and electroencephalogram were suggestive of Angelman syndrome, initial genetic tests were unyielding. Exome sequencing revealed a previously unreported mutation of Ubiquitin Protein Ligase E3A (UBE3A) gene, confirming the diagnosis of Angelman syndrome. The case is aimed to sensitize pediatricians about Angelman syndrome and to highlight the role of sequential investigations in establishing the diagnosis...
December 18, 2017: Indian Journal of Pediatrics
Catherine A Christian
No abstract text is available yet for this article.
July 2017: Epilepsy Currents
Saishruti Kohli, Abhishek Bhardwaj, Richa Kumari, Sanjeev Das
UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor-suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and to epigenetically repress ANXA2 , a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential, and invasiveness of cells...
February 1, 2018: Cancer Research
Huihui Xu, Xing Ji, Yan Xu, Xiaoqing Liu, Jingmin Zhang, Yingwei Chen, Bing Xiao
OBJECTIVE: To explore the genetic cause for two familial Angelman syndrome cases and correlation between the clinical phenotypes and their genetic basis. METHODS: Karyotyping analysis and microarray assay were carried out to exclude chromosome anomalies and uniparental disomy. The UBE3A gene was analyzed for potential point mutations, deletions, insertions and splice site mutations. Reverse transcription PCR was used to evaluate splicing mutation of the RNA transcripts...
December 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Natasha Khatri, James P Gilbert, Yuda Huo, Roozhin Sharaflari, Michael Nee, Hui Qiao, Heng-Ye Man
UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites...
January 10, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Cinthia Aguilera, Marina Viñas-Jornet, Neus Baena, Elisabeth Gabau, Concepción Fernández, Nuria Capdevila, Sanja Cirkovic, Adrijan Sarajlija, Marijana Miskovic, Danijela Radivojevic, Anna Ruiz, Miriam Guitart
BACKGROUND: Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. CASE PRESENTATION: We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis...
November 21, 2017: BMC Medical Genetics
Leeyup Chung, Alexandra L Bey, Aaron J Towers, Xinyu Cao, Il Hwan Kim, Yong-Hui Jiang
Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3am-/p+ ) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3am-/p+ in vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3am-/p+ ...
February 2018: Neurobiology of Disease
Xingxing Xu, Chuanyin Li, Xiaobo Gao, Kun Xia, Hui Guo, Yali Li, Zijian Hao, Lei Zhang, Daming Gao, Chenfan Xu, Huatai Xu, Zhi-Qi Xiong, Zilong Qiu, Ling Mei, Xiaoduo Xie, Kangcheng Ruan, Ronggui Hu
The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity...
January 2018: Cell Research
Marybeth Carmody, Tara P Notarianni, Larissa A Sambel, Shannon J Walsh, Jenna M Burke, Jenna L Armstrong, T Glen Lawson
The encephalomyocarditis virus (EMCV) 3C protease (3Cpro ) is one of a small number of viral proteins whose concentration is known to be regulated by the cellular ubiquitin-proteasome system. Here we report that the ubiquitin-conjugating enzyme UbcH7/UBE2L3 and the ubiquitin-protein ligase E6AP/UBE3A are components of a previously unknown EMCV 3Cpro -polyubiquitylating pathway. Following the identification of UbcH7/UBE2L3 as a participant in 3Cpro ubiquitylation, we purified a UbcH7-dependent 3Cpro -ubiquitylating activity from mouse cells, which we identified as E6AP...
December 9, 2017: Biochemical and Biophysical Research Communications
Brijesh Kumar Singh, Naman Vatsa, Vipendra Kumar, Shashi Shekhar, Ankit Sharma, Nihar Ranjan Jana
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in memory and cognitive function. Pathological hallmark of AD includes aberrant aggregation of amyloid beta (Aβ) peptide, which is produced upon sequential cleavage of amyloid precursor protein (APP) by β- and γ -secretases. On the contrary, α-secretase cleaves APP within the Aβ sequence and thereby prevents Aβ generation. Here, we investigated the role of ubiquitin ligase Ube3a (involved in synaptic function and plasticity) in the pathogenesis of AD using APPswe/PS1δE9 transgenic mouse model and first noticed that soluble pool of Ube3a was age-dependently decreased in AD mouse in comparison with wild type controls...
October 15, 2017: Human Molecular Genetics
Nycole A Copping, Sarah G B Christian, Dylan J Ritter, M Saharul Islam, Nathalie Buscher, Dorota Zolkowska, Michael C Pride, Elizabeth L Berg, Janine M LaSalle, Jacob Ellegood, Jason P Lerch, Lawrence T Reiter, Jill L Silverman, Scott V Dindot
Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum disorder (ASD). Although ∼40 genes are located in the 15q11.2-q13.3 region, overexpression of the ubiquitin-protein E3A ligase (UBE3A) gene is thought to be the predominant molecular cause of the phenotypes observed in Dup15q syndrome...
October 15, 2017: Human Molecular Genetics
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