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https://www.readbyqxmd.com/read/28211971/atypical-angelman-syndrome-due-to-a-mosaic-imprinting-defect-case-reports-and-review-of-the-literature
#1
Anna Le Fevre, Jasmin Beygo, Cheryl Silveira, Benjamin Kamien, Jill Clayton-Smith, Alison Colley, Karin Buiting, Tracy Dudding-Byth
Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non-specific intellectual disability...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28179584/novel-neurobiological-roles-of-ube3a
#2
EDITORIAL
Jiandong Sun, Michel Baudry, Xiaoning Bi
No abstract text is available yet for this article.
February 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28074012/reduced-abundance-of-the-e3-ubiquitin-ligase-e6ap-contributes-to-decreased-expression-of-the-ink4-arf-locus-in-non-small-cell-lung-cancer
#3
Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B Fox, Prudence Russell, Doron Ginsberg, Brendon J Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt
The tumor suppressor p16(INK4a), one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15(INK4b), p16(INK4a), and p19(ARF)) was decreased in E6AP(-/-) mouse embryo fibroblasts...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/28024084/targeting-the-histone-methyltransferase-g9a-activates-imprinted-genes-and-improves-survival-of-a-mouse-model-of-prader-willi-syndrome
#4
Yuna Kim, Hyeong-Min Lee, Yan Xiong, Noah Sciaky, Samuel W Hulbert, Xinyu Cao, Jeffrey I Everitt, Jian Jin, Bryan L Roth, Yong-Hui Jiang
Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m(+)/p(ΔS-U))...
February 2017: Nature Medicine
https://www.readbyqxmd.com/read/28009282/beyond-epilepsy-and-autism-disruption-of-gabrb3-causes-ocular-hypopigmentation
#5
Ryan J Delahanty, Yanfeng Zhang, Terry Jo Bichell, Wangzhen Shen, Kelienne Verdier, Robert L Macdonald, Lili Xu, Kelli Boyd, Janice Williams, Jing-Qiong Kang
Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28007908/topoisomerase-1-inhibitor-topotecan-delays-the-disease-progression-in-a-mouse-model-of-huntington-s-disease
#6
Shashi Shekhar, Naman Vatsa, Vipendra Kumar, Brijesh Kumar Singh, Imran Jamal, Ankit Sharma, Nihar Ranjan Jana
Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27986596/effects-of-the-synthetic-neurosteroid-ganaxolone-on-seizure-activity-and-behavioral-deficits-in-an-angelman-syndrome-mouse-model
#7
Stephanie L Ciarlone, Xinming Wang, Michael A Rogawski, Edwin J Weeber
Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABAA receptors could provide therapeutic benefit. Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks...
December 13, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27974215/cumulative-impact-of-polychlorinated-biphenyl-and-large-chromosomal-duplications-on-dna-methylation-chromatin-and-expression-of-autism-candidate-genes
#8
Keith W Dunaway, M Saharul Islam, Rochelle L Coulson, S Jesse Lopez, Annie Vogel Ciernia, Roy G Chu, Dag H Yasui, Isaac N Pessah, Paul Lott, Charles Mordaunt, Makiko Meguro-Horike, Shin-Ichi Horike, Ian Korf, Janine M LaSalle
Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27860204/angelman-syndrome-current-and-emerging-therapies-in-2016
#9
REVIEW
Wen-Hann Tan, Lynne M Bird
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. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful...
December 2016: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/27819731/liguisticum-wallichii-inhibits-renal-carcinoma-progression-by-downregulating-ube3a-and-through-suppression-of-nf-%C3%AE%C2%BAb-signaling
#10
J S Wu, P M Zhang, L J Sun, X Z Liu
Renal carcinoma accounts for a fifth of the morbidity among malignant tumors in China. Ubiquitin-protein ligase E3A (UBE3A) plays an important role in the occurrence and development of gene mutation-induced diseases. This study was designed to investigate the mechanism of Liguistium wallichii in treating renal carcinoma. Hematoxylin and eosin staining was applied to detect the pathological changes in a rat renal carcinoma model. The experimental group received L. wallichii treatment at 100 mg/kg every 48 h for 4 weeks, while the control group only received normal saline...
November 3, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27771561/proteomic-analysis-of-the-gamma-human-papillomavirus-type-197-e6-and-e7-associated-cellular-proteins
#11
Miranda Grace, Karl Munger
Gamma HPV197 was the most frequently identified HPV when human skin cancer specimens were analyzed by deep sequencing (Arroyo Muhr et al., Int. J. Cancer 136: 2546-55, 2015). To gain insight into the biological activities of HPV197, we investigated the cellular interactomes of HPV197 E6 and E7. HPV197 E6 protein interacts with a broad spectrum of cellular LXXLL domain proteins, including UBE3A and MAML1. HPV197 E6 also binds and inhibits the TP53 tumor suppressor and interacts with the CCR4-NOT ubiquitin ligase and deadenylation complex...
January 2017: Virology
https://www.readbyqxmd.com/read/27769316/neurodevelopmental-profile-in-angelman-syndrome-more-than-low-intelligence-quotient
#12
S Micheletti, F Palestra, P Martelli, P Accorsi, J Galli, L Giordano, V Trebeschi, E Fazzi
BACKGROUND: Angelman Syndrome (AS) is a rare neurodevelopment disorder resulting from deficient expression or function of the maternally inherited allele of UBE3A gene. The aim of the study is to attempt at providing a detailed definition of neurodevelopmental profile in AS, with particular regard to motor, cognitive, communicative, behavioural and neurovisual, features by using standardized instruments. METHOD: A total of ten subjects aged from 5 to 11 years (4 males and 6 females) with molecular confirmed diagnosis of AS (7 15q11...
October 21, 2016: Italian Journal of Pediatrics
https://www.readbyqxmd.com/read/27626634/from-cortical-and-subcortical-grey-matter-abnormalities-to-neurobehavioral-phenotype-of-angelman-syndrome-a-voxel-based-morphometry-study
#13
Gayane Aghakhanyan, Paolo Bonanni, Giovanna Randazzo, Sara Nappi, Federica Tessarotto, Lara De Martin, Francesca Frijia, Daniele De Marchi, Francesco De Masi, Beate Kuppers, Francesco Lombardo, Davide Caramella, Domenico Montanaro
Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures...
2016: PloS One
https://www.readbyqxmd.com/read/27615419/angelman-syndrome-insights-into-a-rare-neurogenetic-disorder
#14
REVIEW
Karin Buiting, Charles Williams, Bernhard Horsthemke
Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect...
October 2016: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/27599063/the-drosophila-melanogaster-homolog-of-ube3a-is-not-imprinted-in-neurons
#15
Kevin A Hope, Mark S LeDoux, Lawrence T Reiter
In mammals, expression of UBE3A is epigenetically regulated in neurons and expression is restricted to the maternal copy of UBE3A. A recent report claimed that Drosophila melanogaster UBE3A homolog (Dube3a) is preferentially expressed from the maternal allele in fly brain, inferring an imprinting mechanism. However, complex epigenetic regulatory features of the mammalian imprinting center are not present in Drosophila, and allele specific expression of Dube3a has not been documented. We used behavioral and electrophysiological analysis of the Dube3a loss-of-function allele (Dube3a(15b)) to investigate Dube3a imprinting in fly neurons...
September 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27581300/environmental-enrichment-improves-behavioral-abnormalities-in-a-mouse-model-of-angelman-syndrome
#16
Imran Jamal, Vipendra Kumar, Naman Vatsa, Brijesh Kumar Singh, Shashi Shekhar, Ankit Sharma, Nihar Ranjan Jana
Angelman syndrome (AS) is a neurodevelopmental disorder largely caused by the loss of function of maternally inherited UBE3A. UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood. Here, we demonstrate that rearing of AS mice in the enriched environment for prolonged period significantly improved their cognitive and motor dysfunction. Enriched environment also restored elevated serum corticosterone level and reduced anxiety-like behaviors in these mice...
September 1, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27537218/a-drosophila-model-of-hpv-e6-induced-malignancy-reveals-essential-roles-for-magi-and-the-insulin-receptor
#17
Mojgan Padash Barmchi, Mary Gilbert, Miranda Thomas, Lawrence Banks, Bing Zhang, Vanessa J Auld
Cervical cancer is one of the leading causes of cancer death in women worldwide. The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation, activities that are believed to contribute towards malignancy. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown...
August 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27517611/cognition-and-synaptic-plasticity-related-changes-in-aged-rats-supplemented-with-8-and-10-carbon-medium-chain-triglycerides
#18
Dongmei Wang, Ellen S Mitchell
Brain glucose hypometabolism is a common feature of Alzheimer's disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats...
2016: PloS One
https://www.readbyqxmd.com/read/27484051/angelman-syndrome-derived-neurons-display-late-onset-of-paternal-ube3a-silencing
#19
Jana Stanurova, Anika Neureiter, Michaela Hiber, Hannah de Oliveira Kessler, Kristin Stolp, Roman Goetzke, Diana Klein, Agnes Bankfalvi, Hannes Klump, Laura Steenpass
Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs)...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27339004/subcellular-organization-of-ube3a-in-neurons
#20
Alain C Burette, Matthew C Judson, Susan Burette, Kristen D Phend, Benjamin D Philpot, Richard J Weinberg
Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains...
February 1, 2017: Journal of Comparative Neurology
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