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  1. Article ; Online: UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome.

    Elgersma, Ype / Sonzogni, Monica

    Developmental medicine and child neurology

    2021  Volume 63, Issue 7, Page(s) 802–807

    Abstract: Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ... ...

    Abstract Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain. Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus. Trials using antisense oligonucleotides to restore UBE3A levels are continuing.
    MeSH term(s) Angelman Syndrome/drug therapy ; Angelman Syndrome/genetics ; Animals ; Disease Models, Animal ; Humans ; Mice ; Oligonucleotides, Antisense/therapeutic use ; Ubiquitin-Protein Ligases/genetics
    Chemical Substances Oligonucleotides, Antisense ; UBE3A protein, human (EC 2.3.2.26) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2021-02-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 80369-8
    ISSN 1469-8749 ; 0012-1622
    ISSN (online) 1469-8749
    ISSN 0012-1622
    DOI 10.1111/dmcn.14831
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Neurodevelopmental disease: A molecular tightrope.

    Elgersma, Ype

    Nature

    2015  Volume 526, Issue 7571, Page(s) 50–51

    MeSH term(s) Angelman Syndrome/genetics ; Animals ; Autistic Disorder/genetics ; Female ; Humans ; Mutation, Missense ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/genetics
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2015-10-01
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/526050b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation.

    Rotaru, Diana C / Wallaard, Ilse / de Vries, Maud / van der Bie, Julia / Elgersma, Ype

    JCI insight

    2023  Volume 8, Issue 4

    Abstract: Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, ... ...

    Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired striatal maturation has been implicated in several mouse models for NDDs, we studied the importance of UBE3A in striatal maturation. We used inducible Ube3a mouse models to investigate the maturation of medium spiny neurons (MSNs) from dorsomedial striatum. MSNs of mutant mice matured properly till postnatal day 15 (P15) but remained hyperexcitable with fewer excitatory synaptic events at later ages, indicative of stalled striatal maturation in Ube3a mice. Reinstatement of UBE3A expression at P21 fully restored MSN excitability but only partially restored synaptic transmission and the operant conditioning behavioral phenotype. Gene reinstatement at P70 failed to rescue both electrophysiological and behavioral phenotypes. In contrast, deletion of Ube3a after normal brain development did not result in these electrophysiological and behavioral phenotypes. This study emphasizes the role of UBE3A in striatal maturation and the importance of early postnatal reinstatement of UBE3A expression to obtain a full rescue of behavioral phenotypes associated with striatal function in AS.
    MeSH term(s) Animals ; Mice ; Angelman Syndrome/genetics ; Brain/metabolism ; Corpus Striatum/metabolism ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Ube3a protein, mouse (EC 2.3.2.26) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2023-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.166073
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Considerations for Clinical Therapeutic Development of Statins for Neurodevelopmental Disorders.

    Ottenhoff, Myrthe J / Krab, Lianne C / Elgersma, Ype

    eNeuro

    2020  Volume 7, Issue 2

    MeSH term(s) Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Lovastatin ; Neurodevelopmental Disorders/drug therapy ; Simvastatin
    Chemical Substances Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Lovastatin (9LHU78OQFD) ; Simvastatin (AGG2FN16EV)
    Language English
    Publishing date 2020-03-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0392-19.2020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: From first report to clinical trials: a bibliometric overview and visualization of the development of Angelman syndrome research.

    Zampeta, F Isabella / Distel, Ben / Elgersma, Ype / Iping, Rik

    Human genetics

    2022  Volume 141, Issue 12, Page(s) 1837–1848

    Abstract: Angelman syndrome is a rare neurodevelopmental disorder caused by mutations affecting the chromosomal 15q11-13 region, either by contiguous gene deletions, imprinting defects, uniparental disomy, or mutations in the UBE3A gene itself. Phenotypic ... ...

    Abstract Angelman syndrome is a rare neurodevelopmental disorder caused by mutations affecting the chromosomal 15q11-13 region, either by contiguous gene deletions, imprinting defects, uniparental disomy, or mutations in the UBE3A gene itself. Phenotypic abnormalities are driven primarily, but not exclusively (especially in 15q11-13 deletion cases) by loss of expression of the maternally inherited UBE3A gene expression. The disorder was first described in 1965 by the English pediatrician Harry Angelman. Since that first description of three children with Angelman syndrome, there has been extensive research into the genetic, molecular and phenotypic aspects of the disorder. In the last decade, this has resulted in over 100 publications per year. Collectively, this research has led the field to a pivotal point in which restoring UBE3A function by genetic therapies is currently explored in several clinical trials. In this study, we employed a bibliometric approach to review and visualize the development of Angelman syndrome research over the last 50 years. We look into different parameters shaping the progress of the Angelman syndrome research field, including source of funding, publishing journals and international collaborations between research groups. Using a network approach, we map the focus of the research field and how that shifted over time. This overview helps understand the shift of research focus in the field and can provide a comprehensive handbook of Angelman syndrome research development.
    MeSH term(s) Child ; Humans ; Angelman Syndrome/genetics ; Angelman Syndrome/therapy ; Ubiquitin-Protein Ligases/genetics ; Mutation ; Bibliometrics ; Chromosomes, Human, Pair 15
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2022-05-30
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 223009-4
    ISSN 1432-1203 ; 0340-6717
    ISSN (online) 1432-1203
    ISSN 0340-6717
    DOI 10.1007/s00439-022-02460-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 256: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation

    Diana C. Rotaru / Ilse Wallaard / Maud de Vries / Julia van der Bie / Ype Elgersma

    JCI Insight, Vol 8, Iss

    2023  Volume 4

    Abstract: Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, ... ...

    Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired striatal maturation has been implicated in several mouse models for NDDs, we studied the importance of UBE3A in striatal maturation. We used inducible Ube3a mouse models to investigate the maturation of medium spiny neurons (MSNs) from dorsomedial striatum. MSNs of mutant mice matured properly till postnatal day 15 (P15) but remained hyperexcitable with fewer excitatory synaptic events at later ages, indicative of stalled striatal maturation in Ube3a mice. Reinstatement of UBE3A expression at P21 fully restored MSN excitability but only partially restored synaptic transmission and the operant conditioning behavioral phenotype. Gene reinstatement at P70 failed to rescue both electrophysiological and behavioral phenotypes. In contrast, deletion of Ube3a after normal brain development did not result in these electrophysiological and behavioral phenotypes. This study emphasizes the role of UBE3A in striatal maturation and the importance of early postnatal reinstatement of UBE3A expression to obtain a full rescue of behavioral phenotypes associated with striatal function in AS.
    Keywords Cell biology ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome.

    Manoubi, Wiem / Mahdouani, Marwa / Hmida, Dorra / Kdissa, Ameni / Rouissi, Aida / Turki, Ilhem / Gueddiche, Neji / Soyah, Najla / Saad, Ali / Bouwkamp, Christian / Elgersma, Ype / Mougou-Zerelli, Soumaya / Gribaa, Moez

    World journal of clinical cases

    2024  Volume 12, Issue 3, Page(s) 503–516

    Abstract: Background: Angelman syndrome (AS) is caused by maternal chromosomal deletions, imprinting defects, paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase : Aim: To investigate the involvement of : Methods: We ... ...

    Abstract Background: Angelman syndrome (AS) is caused by maternal chromosomal deletions, imprinting defects, paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase
    Aim: To investigate the involvement of
    Methods: We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021, with a strong suspicion of AS and absence of chromosomal aberrations. The
    Results: We describe seven
    Conclusion: Screening for
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article
    ISSN 2307-8960
    ISSN 2307-8960
    DOI 10.12998/wjcc.v12.i3.503
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Adult

    Rigter, Pomme M F / Wallaard, Ilse / Aghadavoud Jolfaei, Mehrnoush / Kingma, Jenina / Post, Laura / Elgersma, Minetta / Elgersma, Ype / van Woerden, Geeske M

    iScience

    2022  Volume 25, Issue 11, Page(s) 105303

    Abstract: With the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes a neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there exists a critical ... ...

    Abstract With the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes a neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there exists a critical developmental time window in which CAMK2A needs to be expressed for normal brain development, or whether expression of the protein at later stages is still beneficial to restore normal functioning. To answer this question, we generated an inducible
    Language English
    Publishing date 2022-10-08
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.105303
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  9. Article ; Online: A Novel Automated Approach for Improving Standardization of the Marble Burying Test Enables Quantification of Burying Bouts and Activity Characteristics.

    Wahl, Lucas / Punt, A Mattijs / Arbab, Tara / Willuhn, Ingo / Elgersma, Ype / Badura, Aleksandra

    eNeuro

    2022  Volume 9, Issue 2

    Abstract: The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of ... ...

    Abstract The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), many important characteristics regarding the temporal aspect of this assay are lost. Here, we introduce a novel, automated method to quantify mouse behavior during the marble burying test with the focus on the burying bouts and movement dynamics. Using open-source software packages, we trained a supervised machine learning algorithm (the "classifier") to distinguish burying behavior in freely moving mice. In order to confirm the classifier's accuracy and characterize burying events in high detail, we performed the marble burying test in three mouse models:
    MeSH term(s) Animals ; Behavior, Animal ; Calcium Carbonate ; Disease Models, Animal ; Humans ; Mice ; Nerve Tissue Proteins ; Obsessive-Compulsive Disorder ; Reference Standards
    Chemical Substances Nerve Tissue Proteins ; Sapap3 protein, mouse ; Shank2 protein, mouse ; Calcium Carbonate (H0G9379FGK)
    Language English
    Publishing date 2022-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0446-21.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Angelman Syndrome: From Mouse Models to Therapy.

    Rotaru, Diana C / Mientjes, Edwin J / Elgersma, Ype

    Neuroscience

    2020  Volume 445, Page(s) 172–189

    Abstract: The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, ... ...

    Abstract The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. The pathophysiology of AS is still unclear and a treatment is lacking. Animal models of AS recapitulate the genotypic and phenotypic features observed in AS patients, and have been invaluable for understanding the disease process as well as identifying apropriate drug targets. Using these AS mouse models we have learned that loss of UBE3A probably affects many areas of the brain, leading to increased neuronal excitability and a loss of synaptic spines, along with changes in a number of distinct behaviours. Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS.
    MeSH term(s) Angelman Syndrome/genetics ; Animals ; Disease Models, Animal ; Humans ; Male ; Mice ; Neurons ; Phenotype ; Ubiquitin-Protein Ligases/genetics
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2020-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2020.02.017
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