Research Articles

Below you will find a database containing Research Articles on the Angelman Syndrome/

We try to keep it as much up to date as possible. This is done with a team of people who search the internet or contact researches to ask for permission to post their articles. The articles are placed in their original language, most of the time English.

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Loss of dopaminergic neurons and resulting behavioral deficits in mouse model of Angelman syndrome

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Date added:	08/13/2010
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E6 associated protein is an E3 ubiquitin ligase encoded by the gene Ube3a. Deletion orloss of function of the maternally inherited allele of Ube3a leads to Angelman syndrome.In the present study, we show that maternal loss of Ube3a (Ube3am-/p+) in the mousemodel leads to motor deficits that could be attributed to the dysfunction of thenigrostriatal pathway. The number of tyrosine hydroxylase positive neurons in thesubstantia nigra was significantly reduced in Ube3am-/p+ mice as compared to the wildtype counterparts. The Ube3am-/p+ mice performed poorly in behavioral paradigmssensitive to nigrostriatal dysfunction. Even though the tyrosine hydroxylase staining wasapparently same in the striatum of both genotypes, the presynaptic and postsynapticproteins were significantly reduced in Ube3am-/p+ mice. These findings suggest that theabnormality in the nigrostriatal pathway along with the cerebellum produces the observedmotor dysfunctions in Ube3am-/p+ mice.

Shalaka A. Mulherkar and Nihar Ranjan Jana

Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre,Manesar, Gurgaon - 122 050, India

Altered GABAA Receptor Subunit Expression and Pharmacology in Human Angelman Syndrome Cortex

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Date added:	08/11/2010
Filesize:	259.12 kB
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The neurodevelopmental disorder Angelman syndrome is most frequently causedby deletion of the maternally-derived chromosome 15q11-q13 region, which includes notonly the causative UBE3A gene, but also the beta3-alpha 5-gamma3 GABAA receptor subunit genecluster. GABAergic dysfunction has been hypothesized to contribute to the occurrence ofepilepsy and cognitive and behavioral impairments in this condition. In the present study,analysis of GABAA receptor subunit expression and pharmacology was performed incerebral cortex from four subjects with Angelman syndrome and compared to that fromcontrol tissue. The membrane fraction of frozen postmortem neocortical tissue wasisolated and subjected to quantitative Western blot analysis. The ratios of beta3/beta2 and alpha 5/alpha 1subunit protein expression in Angelman syndrome cortex were significantly decreasedwhen compared with controls. An additional membrane fraction was injected intoXenopus oocytes, resulting in incorporation of the brain membrane vesicles with theirassociated receptors into the oocyte cellular membrane. Two-electrode voltage clampanalysis of GABAA receptor currents was then performed. Studies of GABAA receptorpharmacology in Angelman syndrome cortex revealed increased current enhancement bythe alpha 1-selective benzodiazepine site agonist zolpidem and by the barbituratephenobarbital, while sensitivity to current inhibition by zinc was decreased. GABAAreceptor affinity and modulation by neurosteroids were unchanged. This shift in GABAAreceptor subunit expression and pharmacology in Angelman syndrome is consistent withimpaired extrasynaptic but intact to augmented synaptic cortical GABAergic inhibition,which could contribute to the epileptic, behavioral, and cognitive phenotypes of thedisorder.

W.H. Roden, L.D. Peugh, L.A. Jansen

Neuroscience Letters (2010), doi:10.1016/j.neulet.2010.08.001

Double-Blind Therapeutic Trial in Angelman Syndrome Using Betaine and Folic Acid

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Date added:	08/03/2010
Filesize:	114.04 kB
Downloads:	432

Angelman syndrome (AS) is caused by reduced or absent expressionof the maternally inherited ubiquitin protein ligase 3A gene(UBE3A), which maps to chromosome 15q11–q13. UBE3A issubject to genomic imprinting in neurons in most regions of thebrain. Expression of UBE3A from the maternal chromosome isessential to prevent AS, because the paternally inherited gene isnot expressed, probably mediated by antisense UBE3A RNA. Wehypothesized that increasing methylation might reduce expressionof the antisense UBE3A RNA, thereby increasing UBE3Aexpression from the paternal gene and ameliorating the clinicalphenotype. We conducted a trial using two dietary supplements,betaine and folic acid to promote global levels of methylationand attempt to activate the paternally inherited UBE3A gene.We performed a number of investigations at regular intervalsincluding general clinical and developmental evaluations, biochemicaldeterminations on blood and urine, and electroencephalographicstudies.Wereport herein the data on 48 children withAS who were enrolled in a double-blind placebo-controlledprotocol using betaine and folic acid for 1 year. There were nostatistically significant changes between treated and untreatedchildren; however, in a small subset of patients we observed somepositive trends.

Peters SU, Bird LM, Kimonis V, Glaze DG,Shinawi LM, Bichell TJ, Barbieri-Welge R,Nespeca M, Anselm I, Waisbren S, Sanborn E,Sun Q, O’Brien WE, Beaudet AL, Bacino CA.2010.

Double-blind therapeutic trial inAngelman syndrome using betaine and folicacid.

Am J Med Genet Part A 152A:1994–2001.

Tissue-specific variation of Ube3a protein expression in rodents and in a mousemodel of AS

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Date added:	08/03/2010
Filesize:	1.62 MB
Downloads:	559

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression ormutation-induced dysfunction of its protein product, the E3 ubiquitin–protein ligase, UBE3A. In humans androdents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution ofnative UBE3A/Ube3a1 protein expression has not been comprehensively examined. To address this, wesystematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3amaternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked lossof 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 ofAS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studiesshowed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergicinterneurons as well as principal neurons. These findings suggest that neuronal function throughout thebrain is compromised in AS.

Richard Gustin, Terry Jo Bichell, Michael Bubser, Jennifer Daily, Irina Filonova, Davit Mrelashvili, Ariel Y. Deutch, Roger J. Colbran, Edwin J. Weeber, Kevin F. Haas

Neurobiology of Disease 39 (2010) 283–291

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a

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Date added:	03/10/2010
Filesize:	1.53 MB
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A defect in the maternal copy of a ubiqutin ligase gene Ube3a can produce a neurodevelopmental defect in human children known as Angelman syndrome. We investigated the role of the maternally expressed Ube3a gene in experience-dependent development and plasticity of the mouse visual system. As demonstrated by optical imaging, rapid ocular dominance (OD) plasticity after brief monocular deprivation (MD) was severely impaired during the critical period (CP) in the visual cortex (VC) of Ube3a maternal-deficient (m−/p+) mice. Prolonged MD elicited significant plasticity in m−/ p+ mice that never matched the level seen in control animals. In older animals after the CP, 7-day MD elicited mild OD shifts in both control and m−/p+ mice; however, the OD shifts in m−/p+ mice

lacked the strengthening of visual responses to the two eyes characteristic of normal adult plasticity. Anatomic effects of the maternal deficiency include reduced spine density on basal, but not apical, dendrites of pyramidal neurons in the binocular region of the VC. Imprinting of Ube3a expression was not fully established in the early postnatal period, consistent with the normal development of cortical retinotopy and visual acuity that we observed in

m−/p+ mice, but was fully established by the onset of the CP. These results demonstrate that paternal and maternal genomes are not functionally equivalent for cortical plasticity, and that maternally expressed Ube3a is required for normal experience-dependent modification of cortical circuits during and after the CP. A defect in the maternal copy of a ubiqutin ligase gene Ube3a canproduce a neurodevelopmental defect in human children known asAngelman syndrome. We investigated the role of the maternallyexpressed Ube3a gene in experience-dependent development andplasticity of the mouse visual system. As demonstrated by opticalimaging, rapid ocular dominance (OD) plasticity after brief monoculardeprivation (MD) was severely impaired during the criticalperiod (CP) in the visual cortex (VC) of Ube3a maternal-deficient(m−/p+) mice. Prolonged MD elicited significant plasticity in m−/p+ mice that never matched the level seen in control animals. Inolder animals after the CP, 7-day MD elicited mild OD shifts in bothcontrol and m−/p+ mice; however, the OD shifts in m−/p+ micelacked the strengthening of visual responses to the two eyes characteristicof normal adult plasticity. Anatomic effects of the maternaldeficiency include reduced spine density on basal, but notapical, dendrites of pyramidal neurons in the binocular region ofthe VC. Imprinting of Ube3a expression was not fully established inthe early postnatal period, consistent with the normal developmentof cortical retinotopy and visual acuity that we observed inm−/p+ mice, but was fully established by the onset of the CP. Theseresults demonstrate that paternal and maternal genomes are notfunctionally equivalent for cortical plasticity, and that maternallyexpressed Ube3a is required for normal experience-dependentmodification of cortical circuits during and after the CP.

Masaaki Satoa and Michael P. Strykera

www.pnas.org/cgi/doi/10.1073/pnas.1001281107

Angelman Syndrome: Finding the Lost Arc

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Date added:	03/10/2010
Filesize:	334.89 kB
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Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternally inherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3A substrate called Arc that promotes endocytosis of neuronal AMPA receptors, providing insight into synaptic defects that may underlie the cognitive deficits in Angelman syndrome. Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternallyinherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3Asubstrate called Arc that promotes endocytosis of neuronal AMPA receptors, providing insight intosynaptic defects that may underlie the cognitive deficits in Angelman syndrome.

Hwan-Ching Tai and Erin M. Schuman

The AS-associated ubiquitin ligase Ube3A regulates synapse development by ubiquitinating Arc

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Date added:	03/10/2010
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Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.

Paul L. Greer, Rikinari Hanayama, Brenda L. Bloodgood, Alan R. Mardinly, David M. Lipton, Steven W. Flavell, Tae-Kyung Kim, Eric C. Griffith, Zachary Waldon, Rene Maehr, Hidde L. Ploegh, Shoaib Chowdhury, Paul F. Worley, Judith Steen, Michael E. Greenberg

Cell 140, 704–716, March 5, 2010 ª2010 Elsevier In

Two percent of patients suspected of having Angelman syndrome have TCF4 mutations

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Date added:	03/05/2010
Filesize:	740.61 kB
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The TCF4 gene encodes a basic helix–loop–helix (bHLH) transcription

factor which belongs to the family of E-proteins. E-proteins form homoand

heterodimers with other members of the HLH family and bind to the

common DNA sequence called E-box. Haploinsufficiency of the TCF4

gene has been found to be associated with the Pitt–Hopkins syndrome

(PTHS). PTHS is characterized by severe mental retardation, a wide

mouth plus other distinctive facial features (fleshy lips, beaked nose, broad

nasal bridge) and breathing abnormalities. Because of some phenotypical

overlap with Angelman syndrome (AS), it has been suggested that PTHS

be considered in its differential diagnosis. To explore this possibility, we

screened 86 patients who were suspected of having AS. All the patients

were negative for UBE3A testing, and 53 were known to be negative for

methylation analysis. We identified two TCF4 mutations in this cohort.

The p.S384Tfsx7 mutation lacks the bHLH domain. The p.R582P

mutation lies within the bHLH domain in which seven other missense

mutations have been reported. Both mutations most likely affect the

critical function of the bHLH domain of the TCF4 protein. In summary,

we found two TCF4 mutations in 86 patients (2%) suspected to have AS.

Screening for mutations in this gene should be considered in patients who

present with findings of AS but who have been negative for methylation

and UBE3A testing.

Takano K, Lyons M, Moyes C, Jones J, Schwartz CE.

Clin Genet 2010.

Self-management treatment of drooling: A case series

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Date added:	02/18/2010
Filesize:	283.12 kB
Downloads:	586

J.J.W. Van der Burg ,R. Didden, N. Engbers, P.H. Jongerius, J.J. Rotteveel

J. Behav. Ther. & Exp. Psychiat. 40 (2009) 106–119

Behavioral treatment of drooling is advocated widely, but evidence

of its effectiveness is lacking. In a center-based case-series study,

10 participants with severe drooling were taught self-management

skills to reduce drooling. Following treatment, all participants

remained dry for intervals of 30–60 min, while being engaged in

daily activities. Generalization to the classroom occurred in each

participant. For three participants, maintenance of treatment effect

was established at 6 and 24 weeks. Seven participants failed to

maintain self-management skills at follow-up. Although the selfmanagement

procedure showed promising results, further

adaptations are required to improve efficacy, generalization, and

maintenance.

Manuelle Medizin bei Patienten mit Angelman-Syndrom

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Date added:	02/15/2010
Filesize:	100.09 kB
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M.Riedel · H. Lohse-Busch · Rheintalklinik, Bad Krozingen

Ebenso wie bei Patienten mit anderen zerebralen Bewegungsstörungen entwickeln sich beim Angelman-Syndrom (AS) im Laufe der Zeit über die eigentliche Ursache des genetischen Defektes hinaus erhebliche Sekundärstörungen

an Muskeln, Bändern und Gelenken. Unter Berücksichtigung der biomechanischen

und entwicklungsneurologischen Grenzen, die durch das genetische Defektsyndrom vorgegebenen werden, können mit geeigneten Mitteln der Manuellen Medizin sekundäre Funktionsstörungen auch bei diesen

Patienten gemindert werden. Methoden: Retrospektiv wurden bei 12 Kindern

(6 weibl., 6 männl.,Durchschnittsalter 4,5 Jahre) mit gesichertem Angelman-Syndrom die Behandlungsfolgen einer 2wöchigen ambulanten Komplextherapie unter Einschluss der Manuellen Medizin überprüft.

Ergebnisse: Alle Kinder haben sich in den vorgegebenen Therapiezielen verbessert. Die Eltern sind sich sicher, dass ein erneuter Behandlungsblock eine weitere Besserung bringen werde. Die vorgestellten Ergebnisse zeigen, dass mit der Manuellen Medizin bei Kindern mit Angelman-Syndrom eine Besserung der Lebensqualität erwartet werden darf.