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Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.
Grier MD, Carson RP, Lagrange AH
(2015) Behav Brain Res 291: 260-267
MeSH Terms: Angelman Syndrome, Animals, Cerebral Cortex, Diet, High-Fat, Disease Models, Animal, Female, Heterozygote, Male, Maternal Nutritional Physiological Phenomena, Mice, Inbred C57BL, Mice, Knockout, Myelin Proteins, Phenotype, Receptors, Glucocorticoid, Sciatic Nerve, Spinal Cord, Ubiquitin-Protein Ligases
Show Abstract · Added March 14, 2018
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype.
Published by Elsevier B.V.
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17 MeSH Terms
Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.
Grier MD, Carson RP, Lagrange AH
(2015) PLoS One 10: e0124649
MeSH Terms: Alleles, Angelman Syndrome, Animals, Astrocytes, Brain, Cell Extracts, Cells, Cultured, Disease Models, Animal, Female, Gene Silencing, Genomic Imprinting, Humans, Male, Mice, Mice, Inbred C57BL, Neuroglia, Oligodendroglia, Sciatic Nerve, Spinal Cord, Time Factors, Ubiquitin-Protein Ligases
Show Abstract · Added March 14, 2018
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.
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21 MeSH Terms
Ube3a imprinting impairs circadian robustness in Angelman syndrome models.
Shi SQ, Bichell TJ, Ihrie RA, Johnson CH
(2015) Curr Biol 25: 537-45
MeSH Terms: ARNTL Transcription Factors, Analysis of Variance, Angelman Syndrome, Animals, Body Weight, Chronotherapy, Circadian Rhythm, Gene Deletion, Genomic Imprinting, Humans, Liver, Mice, Neurons, Sleep Wake Disorders, Ubiquitin-Protein Ligases
Show Abstract · Added February 12, 2015
BACKGROUND - The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS.
RESULTS - We found a unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS-model mice, indicating an important role for Ube3a in modulating BMAL1 turnover.
CONCLUSIONS - Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Sleep in children and adolescents with Angelman syndrome: association with parent sleep and stress.
Goldman SE, Bichell TJ, Surdyka K, Malow BA
(2012) J Intellect Disabil Res 56: 600-8
MeSH Terms: Actigraphy, Adolescent, Angelman Syndrome, Caregivers, Child, Child, Preschool, Family Health, Female, Humans, Male, Parents, Polysomnography, Sleep, Sleep Disorders, Circadian Rhythm, Sleep Initiation and Maintenance Disorders, Stress, Psychological, Surveys and Questionnaires
Show Abstract · Added March 20, 2014
BACKGROUND - Sleep concerns are common in children with Angelman syndrome, with 20-80% of individuals having a decreased sleep need and/or abnormal sleep-wake cycles. The impact of these sleep behaviours on parental sleep and stress is not known.
METHOD - Through the use of standardised questionnaires, wrist actigraphy and polysomnography, we defined the sleep behaviours of 15 children/adolescents with Angelman syndrome and the association of the child/adolescents sleep behaviours on parental sleep behaviours and parental stress.
RESULTS - Both children/adolescents and their parents exhibited over 1 h of wake time after sleep onset and fragmented sleep. Prolonged sleep latency in the child was associated with parent insomnia and daytime sleepiness. Additionally, variability in child total sleep time was associated with parental stress.
CONCLUSIONS - Poor sleep in children/adolescents with Angelman syndrome was associated with poor parental sleep and higher parental stress. Further work is warranted to identify the underlying causes of the poor sleep, and to relate these findings to daytime functioning, behaviour and the family unit.
© 2011 The Authors. Journal of Intellectual Disability Research © 2011 Blackwell Publishing Ltd.
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17 MeSH Terms
Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome.
Gustin RM, Bichell TJ, Bubser M, Daily J, Filonova I, Mrelashvili D, Deutch AY, Colbran RJ, Weeber EJ, Haas KF
(2010) Neurobiol Dis 39: 283-91
MeSH Terms: Analysis of Variance, Angelman Syndrome, Animals, Blotting, Western, Brain, Disease Models, Animal, Immunohistochemistry, Liver, Mice, Mice, Knockout, Myocardium, Neurons, Tissue Distribution, Ubiquitin-Protein Ligases, gamma-Aminobutyric Acid
Show Abstract · Added March 20, 2014
Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a(1) protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactory bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studies showed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergic interneurons as well as principal neurons. These findings suggest that neuronal function throughout the brain is compromised in AS.
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15 MeSH Terms
Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.
Nurmi EL, Bradford Y, Chen Y, Hall J, Arnone B, Gardiner MB, Hutcheson HB, Gilbert JR, Pericak-Vance MA, Copeland-Yates SA, Michaelis RC, Wassink TH, Santangelo SL, Sheffield VC, Piven J, Folstein SE, Haines JL, Sutcliffe JS
(2001) Genomics 77: 105-13
MeSH Terms: Alleles, Angelman Syndrome, Autistic Disorder, Base Sequence, Chromosome Deletion, Chromosomes, Human, Pair 15, DNA, DNA Mutational Analysis, Family Health, Female, Gene Frequency, Genotype, Humans, Ligases, Linkage Disequilibrium, Male, Microsatellite Repeats, Molecular Sequence Data, Polymorphism, Single Nucleotide, Protein Subunits, Receptors, GABA-A, Sequence Deletion, Ubiquitin-Protein Ligases
Show Abstract · Added February 20, 2014
Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.
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23 MeSH Terms
The spectrum of mutations in UBE3A causing Angelman syndrome.
Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, Christian SL, Kubota T, Halley DJ, Meijers-Heijboer H, Langlois S, Graham JM, Beuten J, Willems PJ, Ledbetter DH, Beaudet AL
(1999) Hum Mol Genet 8: 129-35
MeSH Terms: Angelman Syndrome, Animals, Base Sequence, DNA Mutational Analysis, DNA Primers, Exons, Female, Genetic Counseling, Genetic Variation, Genomic Imprinting, Humans, Ligases, Male, Mice, Mutation, Pedigree, Phenotype, Ubiquitin-Protein Ligases
Show Abstract · Added February 20, 2014
Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.
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18 MeSH Terms
Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb.
Christian SL, Bhatt NK, Martin SA, Sutcliffe JS, Kubota T, Huang B, Mutirangura A, Chinault AC, Beaudet AL, Ledbetter DH
(1998) Genome Res 8: 146-57
MeSH Terms: Angelman Syndrome, Base Composition, Chromosome Mapping, Chromosomes, Artificial, Yeast, Chromosomes, Human, Pair 15, Genetic Markers, Humans, Polymorphism, Genetic, Prader-Willi Syndrome, Sequence Tagged Sites
Show Abstract · Added February 20, 2014
Prader-Willi syndrome and Angelman syndrome are associated with parent-of-origin-specific abnormalities of chromosome 15q11-q13, most frequently a deletion of an approximately 4-Mb region. Because of genomic imprinting, paternal deficiency of this region leads to PWS and maternal deficiency to AS. Additionally, this region is frequently involved in other chromosomal rearrangements including duplications, triplications, or supernumerary marker formation. A detailed physical map of this region is important for elucidating the genes and mechanisms involved in genomic imprinting, as well as for understanding the mechanism of recurrent chromosomal rearrangments. An initial YAC contig extended from D15S18 to D15S12 and was comprised of 23 YACs and 21 STSs providing an average resolution of about one STS per 200 kb. To close two gaps in this contig, YAC screening was performed using two STSs that flank the gap between D15S18 and 254B5R and three STSs located distal to the GABRA5-149A9L gap. Additionally, we developed 11 new STSs, including seven polymorphic markers. Although several groups have developed whole-genome genetic and radiation hybrid maps, the depth of coverage for 15q11-q13 has been somewhat limited and discrepancies in marker order exist between the maps. To resolve the inconsistencies and to provide a more detailed map order of STSs in this region, we have constructed an integrated YAC STS-based physical map of chromosome 15q11-q13 containing 118 YACs and 118 STSs, including 38 STRs and 49 genes/ESTs. Using an estimate of 4 Mb for the size of this region, the map provides an average STS spacing of 35 kb. This map provides a valuable resource for identification of disease genes localized to this region as well as a framework for complete DNA sequencing.
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10 MeSH Terms
Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.
Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G, Beaudet AL
(1997) Nat Genet 17: 75-8
MeSH Terms: Angelman Syndrome, Animals, Cerebellum, Chromosome Mapping, Chromosomes, Human, Pair 15, Embryo, Mammalian, Female, Gene Expression, Genomic Imprinting, Hippocampus, Humans, Ligases, Male, Mice, Mice, Inbred ICR, Molecular Sequence Data, Neurons, Purkinje Cells, Sex Characteristics, Translocation, Genetic, Ubiquitin-Protein Ligases
Show Abstract · Added February 20, 2014
Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.
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21 MeSH Terms
The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region.
Sutcliffe JS, Jiang YH, Galijaard RJ, Matsuura T, Fang P, Kubota T, Christian SL, Bressler J, Cattanach B, Ledbetter DH, Beaudet AL
(1997) Genome Res 7: 368-77
MeSH Terms: Amino Acid Sequence, Angelman Syndrome, Animals, Blotting, Northern, Blotting, Southern, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Artificial, Yeast, Chromosomes, Human, Pair 15, Cloning, Molecular, Cosmids, Electrophoresis, Gel, Pulsed-Field, Female, Gene Deletion, Gene Dosage, Gene Expression Regulation, Developmental, Genetic Markers, Genomic Imprinting, Humans, In Situ Hybridization, Ligases, Male, Mice, Mice, Mutant Strains, Molecular Sequence Data, Paternity, Prader-Willi Syndrome, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Tissue Distribution, Transcription, Genetic, Translocation, Genetic, Ubiquitin-Protein Ligases
Show Abstract · Added February 20, 2014
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct clinical phenotypes resulting from maternal and paternal deficiencies, respectively, in human chromosome 15qll-q13. Although several imprinted, paternally expressed transcripts have been identified within the PWS candidate region, no maternally expressed gene has yet been identified within the AS candidate region. We have developed an integrated physical map spanning the PWS and AS candidate regions and localized two breakpoints, including a cryptic t(14;15) translocation associated with AS and a non-AS 15q deletion, which substantially narrow the AS candidate region to approximately 250 kb. Mapping data indicate that the entire transcriptional unit of the E6-AP ubiquitin-protein ligase (UBE3A) gene lies within the AS region. The UBE3A locus expresses a transcript of approximately 5 kb at low to moderate levels in all tissues tested. The mouse homolog of UBE3A was cloned and sequenced revealing a high degree of conservation at nucleotide and protein levels. Northern and RT-PCR analysis of Ube3a expression in mouse tissues from animals with segmental, paternal uniparental disomy failed to detect substantially reduced or absent expression compared to control animals, failing to provide any evidence for maternal-specific expression from this locus. Recent identification of de novo truncating mutations in UBE3A taken with these observations indicates that mutations in UBE3A can lead to AS and suggests that this locus may encode both imprinted and biallelically expressed products.
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33 MeSH Terms