subject:(UBE3A)

Boston University

1. Magsino, Emmanuel. Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons.

Degree: MS, Medical Sciences, 2016, Boston University

► UBE3A is a protein with dual functions as an E3 ubiquitin ligase and as a Steroid Hormone Receptor (SHR) transcriptional coactivator. It is expressed ubiquitously… (more)

▼ UBE3A is a protein with dual functions as an E3 ubiquitin ligase and as a Steroid Hormone Receptor (SHR) transcriptional coactivator. It is expressed ubiquitously in tissues and has significant importance in neurons, where it is expressed exclusively from the maternal allele. Thus, while UBE3A has a wide variety of targets in various tissues, it is especially important in the brain as UBE3A regulates several aspects of neuronal growth, function, and maintenance. Therefore deficits of Ube3a cause Angelman Syndrome (AS) and increased dosage causes Autism Spectrum Disorder (ASD), two neurological disorders. The pathological phenotype of both diseases involves behavioral dysfunctions in learning, motor skills, and sociability. Through microarray studies, our laboratory has found that Ube3a is involved in the regulation of neuronal proteins such as CBLN1, which has been found to have significant importance in parallel fiber synapse formation onto Purkinje cells. To determine how regulation of CBLN1 occurs, mutant variants of human Ube3a isoform III were then generated. E3 ligase-dead, substrate-binding defective, nonphosphorylatable mutant, and phosphor-mimetic mutants were produced and inserted into a pLVX-IRES-mCherry vector. A quantitative transcriptional analysis demonstrated that increasing wild-type (WT) UBE3A decreased Cbln1 expression. The ligase dead mutant mimicked the WT suggesting that E3 ligase activity is not required in the regulation of Cbln1. The nonphosphorylatable mutant demonstrated an increase in Cbln1 expression, which may be due to a dominant negative effect on native UBE3A causing its degradation. The phosphor-mimetic mutant had no statistical effect. This may be due to its inability to enter the nucleus and affect transcription. The substrate-binding mutant also showed no statistical effect possibly because of its inability to bind to any substrate and that may be necessary to regulate transcription. These preliminary results demonstrate that UBE3A may be regulating CBLN1 at the transcriptional level independent of its E3 ubiquitin ligase function. Future studies will be required to more precisely determine the mechanisms involved in UBE3A’s regulation of CBLN1.

Subjects/Keywords: Neurosciences; Angelman; Autism; Ube3a

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Magsino, E. (2016). Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16757

Chicago Manual of Style (16^th Edition):

Magsino, Emmanuel. “Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons.” 2016. Masters Thesis, Boston University. Accessed March 08, 2021. http://hdl.handle.net/2144/16757.

MLA Handbook (7^th Edition):

Magsino, Emmanuel. “Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons.” 2016. Web. 08 Mar 2021.

Vancouver:

Magsino E. Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons. [Internet] [Masters thesis]. Boston University; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/2144/16757.

Council of Science Editors:

Magsino E. Investigating the role of autism gene Ube3a in the transcriptional regulation in neurons. [Masters Thesis]. Boston University; 2016. Available from: http://hdl.handle.net/2144/16757

University of South Florida

2. Daily, Jennifer L. Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse.

Degree: 2012, University of South Florida

URL: https://scholarcommons.usf.edu/etd/4305

► Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia.… (more)

Subjects/Keywords: Angelman; hippocampus; proteasome; UBE3A; Neurosciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Daily, J. L. (2012). Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse. (Thesis). University of South Florida. Retrieved from https://scholarcommons.usf.edu/etd/4305

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Daily, Jennifer L. “Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse.” 2012. Thesis, University of South Florida. Accessed March 08, 2021. https://scholarcommons.usf.edu/etd/4305.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Daily, Jennifer L. “Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse.” 2012. Web. 08 Mar 2021.

Vancouver:

Daily JL. Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse. [Internet] [Thesis]. University of South Florida; 2012. [cited 2021 Mar 08]. Available from: https://scholarcommons.usf.edu/etd/4305.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Daily JL. Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse. [Thesis]. University of South Florida; 2012. Available from: https://scholarcommons.usf.edu/etd/4305

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Boston University

3. Cruz, Tristan. Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression.

Degree: MS, Medical Sciences, 2017, Boston University

URL: http://hdl.handle.net/2144/23772

► BACKGROUND: Cbln1 is a gene whose expression is negatively correlated to seizures. Krishnan et al. has recently shown that seizures synergize with transcriptional co-regulator Ube3a… (more)

Subjects/Keywords: Neurosciences; Cbln1; RE-1; Ube3a; Autism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cruz, T. (2017). Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/23772

Chicago Manual of Style (16^th Edition):

Cruz, Tristan. “Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression.” 2017. Masters Thesis, Boston University. Accessed March 08, 2021. http://hdl.handle.net/2144/23772.

MLA Handbook (7^th Edition):

Cruz, Tristan. “Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression.” 2017. Web. 08 Mar 2021.

Vancouver:

Cruz T. Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression. [Internet] [Masters thesis]. Boston University; 2017. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/2144/23772.

Council of Science Editors:

Cruz T. Role of CBLN1’S RE-1 transcriptional regulatory sequences in gene repression. [Masters Thesis]. Boston University; 2017. Available from: http://hdl.handle.net/2144/23772

UCLA

4. Frohlich, Joel. Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders.

Degree: Neuroscience, 2018, UCLA

URL: http://www.escholarship.org/uc/item/42v279t0

► Mechanism-based biomarkers are needed to guide clinical trials for neurodevelopmental disorders by indexing disease pathology or a treatment response. In this dissertation, I describe electroencephalogram… (more)

▼ Mechanism-based biomarkers are needed to guide clinical trials for neurodevelopmental disorders by indexing disease pathology or a treatment response. In this dissertation, I describe electroencephalogram (EEG) biomarkers in two neurodevelopmental disorders, Dup15q syndrome and Angelman syndrome. Dup15q syndrome is caused by duplications of 15q11.2-q13.1, including UBE3A—a paternally imprinted gene involved in synapse development—and several gamma-aminobutyric acid type-A (GABA-A) receptor subunit genes. In Angelman syndrome, the majority of cases are caused by deletions of 15q11.2-q13.1, though some cases are caused by UBE3A dysfunction alone. Both disorders are characterized by epilepsy, intellectual disability, and phenotypic overlap with autism spectrum disorder (ASD).In Chapter 1, I introduce biomarkers and neurodevelopmental disorders. In Chapter 2, I infer the emergence of stable oscillations from neural noise in typically developing (TD) preschool age children. In Chapter 3, I describe a beta EEG phenotype of Dup15q syndrome, which distinguishes children with this disorder from TD and nonsyndromic ASD controls. In Chapter 4, I compare this phenotype with beta oscillations induced with midazolam, a GABA-A modulator, in healthy adult participants. Furthermore, two cases of paternal Dup15q syndrome (i.e., duplications of the UBE3A-silenced allele) also show this EEG phenotype, suggesting that it is a marker of GABAergic pathology. In Chapter 5, I describe a delta EEG phenotype of Angelman syndrome (previously described by Sidorov and colleagues in 2017) that is stronger in children with a deletion genotype than those with a non-deletion genotype. Furthermore, I find lower beta power and higher theta power in the deletion genotype. Thus, beta power and theta power appear to reflect GABAergic dysfunction, whereas delta power appears to reflect UBE3A dysfunction but is modulated by GABA-A receptor gene deletion. Chapter 6 summarizes this work and provides a discussion about implications and next steps. In conclusion, neurophysiological oscillations are likely markers of gene-specific disease pathology in Dup15q syndrome and Angelman syndrome. Clinical trials targeting specific gene products (e.g., GABA-A receptors) may utilize these EEG measures as biomarkers of target engagement or surrogate endpoints.

Subjects/Keywords: Neurosciences; Genetics; Angelman syndrome; Biomarker; Dup15q syndrome; EEG; GABA; UBE3A

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Frohlich, J. (2018). Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/42v279t0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Frohlich, Joel. “Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders.” 2018. Thesis, UCLA. Accessed March 08, 2021. http://www.escholarship.org/uc/item/42v279t0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Frohlich, Joel. “Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders.” 2018. Web. 08 Mar 2021.

Vancouver:

Frohlich J. Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders. [Internet] [Thesis]. UCLA; 2018. [cited 2021 Mar 08]. Available from: http://www.escholarship.org/uc/item/42v279t0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Frohlich J. Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders. [Thesis]. UCLA; 2018. Available from: http://www.escholarship.org/uc/item/42v279t0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

5. Hope, Kevin A. Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome.

Degree: PhD, Biomedical Sciences, 2019, University of Tennessee Health Science Center

URL: https://dc.uthsc.edu/dissertations/489

► Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region and is characterized by developmental delay, autism spectrum disorder,… (more)

▼ Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region and is characterized by developmental delay, autism spectrum disorder, and treatment resistant epilepsy. Extra copies of the E3 ubiquitin ligase UBE3A and elevated levels of UBE3A expression in neurons are thought to be the primary cause of Dup15q phenotypes. However, animal models overexpressing UBE3A in neurons have not successfully recapitulated all aspects of Dup15q syndrome, especially epilepsy. Here, we used Drosophila melanogaster (fruit flies) to investigate Dup15q syndrome. In Chapter 2 we explored whether Dube3a, the Drosophila homolog of UBE3A, is imprinted in the fly brain. In mammals, UBE3A undergoes complex imprinting and is expressed only from the maternal allele in mature neurons. Prior to this work the imprinting status of Dube3a in flies was unclear. Here, we present evidence that Dube3a is not imprinted and is biallelically expressed in the fly. Next, in Chapter 3 we examined the interaction between Dube3a and HERC2. HERC2 is also an E3 ubiquitin ligase located in the 15q11.2-q13.1 critical region and is duplicated in all Dup15q individuals. HERC2 physically interacts with and stimulates the ubiquitin ligase activity of UBE3A in vitro. We found that Drosophila HERC2 appears to stimulate the ubiquitin ligase function of Dube3a, and Dube3a and HERC2 interact synergistically to impact phenotypes associated with Dup15q syndrome in vivo. Data presented in Chapter 3 suggests that genes other than UBE3A are important in generating the Dup15q phenotypes and should not be ignored when modeling Dup15q syndrome. In Chapter 4 we investigated how non-neuronal cells, specifically glial cells, contribute to the seizure phenotype of Dup15q syndrome. We found that elevated levels of Dube3a or UBE3A in glia causes seizures, while overexpression in neurons does not. These data are consistent with mammalian models in which UBE3A elevation in neurons does not generate seizures. Furthermore, overexpression of Dube3a in glia reduced protein levels of the Na+/K+ ATPase, ATPα. ATPα down regulation in glia is both necessary and sufficient to generate seizures. In Chapter 5 we further characterized our Dup15q epilepsy model and investigated cell type specific effects of Dube3a overexpression in glia compared to neurons using whole transcriptome and whole proteome analyses. We found that elevation of Dube3a in glia caused a cell non-autonomous down regulation of synaptic proteins in neurons while simultaneously causing a cell autonomous upregulation of glutathione S-transferases (GSTs) in glial cells. Finally, we showed that the upregulation of GSTs is common to multiple different Drosophila gliopathic seizure lines, not just our Dup15q epilepsy model. GSTs play a role in drug metabolism, and elevation of these enzymes may underlie the treatment resistant nature of some epilepsies including Dup15q syndrome. The results from these studies highlight the role that glial cell dysfunction may play in generating seizures in… Advisors/Committee Members: Lawrence T. Reiter, Ph.D..

Subjects/Keywords: Drosophila; Dube3a; Dup15q; Seizure; UBE3A; Medicine and Health Sciences; Neurosciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hope, K. A. (2019). Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/489

Chicago Manual of Style (16^th Edition):

Hope, Kevin A. “Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome.” 2019. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed March 08, 2021. https://dc.uthsc.edu/dissertations/489.

MLA Handbook (7^th Edition):

Hope, Kevin A. “Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome.” 2019. Web. 08 Mar 2021.

Vancouver:

Hope KA. Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2019. [cited 2021 Mar 08]. Available from: https://dc.uthsc.edu/dissertations/489.

Council of Science Editors:

Hope KA. Investigation of Cell-Type-Specific Effects and Synergistic Interactions Between Genes in Duplication 15q Syndrome. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2019. Available from: https://dc.uthsc.edu/dissertations/489

Arizona State University

6. Li, Guohui. Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model.

Degree: Neuroscience, 2017, Arizona State University

URL: http://repository.asu.edu/items/44228

► Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delays, intellectual disabilities, impaired language and speech, and movement defects. Most AS cases are caused… (more)

▼ Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delays, intellectual disabilities, impaired language and speech, and movement defects. Most AS cases are caused by dysfunction of a maternally-expressed E3 ubiquitin ligase (UBE3A, also known as E6 associated protein, E6-AP) in neurons. Currently, the mechanism on how loss-of-function of the enzyme influences the nervous system development remains unknown. We hypothesize that impaired metabolism of proteins, most likely those related to E6-AP substrates, may alter the developmental trajectory of neuronal structures including dendrites, spines and synaptic proteins, which leads to disrupted activity/experience-dependent synaptic plasticity and maturation. To test this hypothesis, we conducted a detailed investigation on neuronal morphology and electrophysiological properties in the prefrontal cortex (PFC) layer 5 (L5) corticostriatal pyramidal neurons (target neurons). We found smaller soma size in the maternal Ube3a deficient mice (m-/p+; 'AS' mice) at postnatal 17-19 (P17-19), P28-35 and older than 70 days (>P70), and decreased basal dendritic processes at P28-35. Surprisingly, both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) decreased on these neurons. These neurons also exhibited abnormalities in the local neural circuits, short-term synaptic plasticity and AMPA/NMDA ratio: the excitatory inputs from L2/3 and L5A, and inhibitory inputs from L5 significantly reduced in AS mice from P17-19; Both the release probability (Pr) and readily-releasable vesicle (RRV) pool replenishment of presynaptic neurons of the target neurons were disrupted at P17-19 and P28-35, and the change of RRV pool replenishment maintained through adulthood (>P70). The AMPA/NMDA ratio showed abnormality in the L5 corticostriatal neurons of PFC in AS mice older than P28-35, during which it decreased significantly compared to that of age-matched WT littermates. Western Blot analysis revealed that the expression level of a key regulator of the cytoskeleton system, Rho family small GTPase cell division control protein 42 homolog (cdc42), reduced significantly in the PFC of AS mice at P28-35.These impairments of synaptic transmission and short-term synaptic plasticity may account for the impaired neuronal morphology and synaptic deficits observed in the PFC target neurons, and contribute to the phenotypes in AS model mice. The present work reveals for the first time that the E6-AP deficiency influences brain function in both brain region-specific and age-dependent ways, demonstrates the functional impairment at the neural circuit level, and reveals that the presynaptic mechanisms are disrupted in AS model. These novel findings shed light on our understanding of the AS pathogenesis and inform potential novel therapeutic explorations.

Subjects/Keywords: Neurosciences; Angelman syndrome; Synaptic plasticity; Synaptic transmission; Ube3a

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, G. (2017). Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model. (Doctoral Dissertation). Arizona State University. Retrieved from http://repository.asu.edu/items/44228

Chicago Manual of Style (16^th Edition):

Li, Guohui. “Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model.” 2017. Doctoral Dissertation, Arizona State University. Accessed March 08, 2021. http://repository.asu.edu/items/44228.

MLA Handbook (7^th Edition):

Li, Guohui. “Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model.” 2017. Web. 08 Mar 2021.

Vancouver:

Li G. Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model. [Internet] [Doctoral dissertation]. Arizona State University; 2017. [cited 2021 Mar 08]. Available from: http://repository.asu.edu/items/44228.

Council of Science Editors:

Li G. Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model. [Doctoral Dissertation]. Arizona State University; 2017. Available from: http://repository.asu.edu/items/44228

7. Cruvinel, Estela Mitie. Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman.

Degree: Mestrado, Biologia (Genética), 2011, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22092011-135856/ ;

►

Síndrome de Angelman (AS - MIM 105830) é causada pela ausência de função do gene UBE3A que codifica uma proteína ubiquitina - ligase (E6-AP). Esse… (more)

▼

Síndrome de Angelman (AS - MIM 105830) é causada pela ausência de função do gene UBE3A que codifica uma proteína ubiquitina - ligase (E6-AP). Esse gene é expresso bialelicamente em vários tecidos exceto no cérebro, onde a expressão é preferencialmente materna. O RNA anti-senso de UBE3A é considerado o regulador dessa expressão diferencial entre os alelos, e faz parte de um transcrito grande que só o alelo paterno é expresso devido ao imprinting genômico; no cérebro, esse transcrito se entende até a região anti-senso de UBE3A, mas nos demais tecidos o transcrito é menor e não engloba a região anti-senso. Este trabalho visa obter um modelo para estudo da AS. Células-tronco da polpa do dente (SHEDs) de pacientes com deleção do segmento 15q11-q13 ou mutação no gene UBE3A foram caracterizadas e submetidas à diferenciação neuronal. A diferenciação foi analisada através do estudo de RNA e proteínas para marcadores neuronais e, também, por testes funcionais. As SHEDs são células-tronco mesenquimais e constituem uma população heterogênea. Essas células ou algumas dessas células já expressam algumas proteínas neuronais ou de células excitáveis como nestina, β-tubulina III, MAP2 e proteína de canais dependentes de voltagem de sódio e potássio. Um ponto interessante é que as SHEDs apresentam baixa expressão do UBE3A anti-senso e a expressão do UBE3A nas células de pacientes é menor que 50% da expressão encontrada nas células de controles, que pode indicar a ocorrência de expressão preferencial materna desse gene em outros tipos celulares além de neurônios maduros. Quando induzidas à diferenciação neurogênica, a maioria das linhagens controles apresentou aumento da expressão de MAP2 e, principalmente, β-tubulina III; e a maioria das linhagens de pacientes com AS não apresentou aumento notável na expressão dessas proteínas, exceto uma linhagem de paciente que aumentou a expressão de β-tubulina III. As células induzidas à diferenciação apresentaram aumento estatisticamente significativo da condutância de sódio através de canais de sódio dependentes de voltagem. Com a análise de expressão de UBE3A e do UBE3A anti-senso é possível afirmar que a expressão deles não alterou com a diferenciação neuronal. Assim, é possível concluir que as células-tronco da polpa do dente, com o protocolo de diferenciação neurogênica, progrediram na via de diferenciação, mas a maioria das células não atingiu o estágio de maturação necessário para que ocorresse o imprinting do UBE3A ou a via de diferenciação não ia em direção a neurônios que apresentam imprinting do UBE3A.

Angelman syndrome (AS - MIN 105830) is caused by the loss of function of the maternal UBE3A gene, which encodes an ubiquitin protein ligase (E6-AP). UBE3A displays biallelic expression in most of tissues, but maternal predominant expression is observed in the brain. A RNA antisense that is paternally expressed in some regions in the brain is considered to be responsible for this tissue-specific imprinting; UBE3A antisense is part of a large transcript that starts at…

Advisors/Committee Members: Koiffmann, Celia Priszkulnik.

Subjects/Keywords: Angelman syndrome; Células-tronco de polpa de dente; Dental pulp stem cells; Diferenciação neurogênica; Genomic imprinting; Imprinting genômico; Neuronal differentiation; Síndrome de Angelman; UBE3A; UBE3A

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cruvinel, E. M. (2011). Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22092011-135856/ ;

Chicago Manual of Style (16^th Edition):

Cruvinel, Estela Mitie. “Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman.” 2011. Masters Thesis, University of São Paulo. Accessed March 08, 2021. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22092011-135856/ ;.

MLA Handbook (7^th Edition):

Cruvinel, Estela Mitie. “Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman.” 2011. Web. 08 Mar 2021.

Vancouver:

Cruvinel EM. Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman. [Internet] [Masters thesis]. University of São Paulo; 2011. [cited 2021 Mar 08]. Available from: http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22092011-135856/ ;.

Council of Science Editors:

Cruvinel EM. Estudo de expressão do gene UBE3A em neurônios derivados de células-tronco da polpa dentária de pacientes com a síndrome de Angelman. [Masters Thesis]. University of São Paulo; 2011. Available from: http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22092011-135856/ ;

Universidade Nova

8. Joaquim, Mariana Isabel Lopes. Exploring cell reprogramming techniques for Angelman Syndrome disease modelling.

Degree: 2017, Universidade Nova

URL: https://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/42365

► Angelman Syndrome (AS) is an imprinted neurodevelopmental disease with no cure caused by the lack of UBE3A expression, which, in neurons, is exclusively maternally expressed.… (more)

▼ Angelman Syndrome (AS) is an imprinted neurodevelopmental disease with no cure caused by the lack of UBE3A expression, which, in neurons, is exclusively maternally expressed. The paternal UBE3A allele is silenced by the UBE3A antisense transcript (UBE3A-ATS), which is only expressed from the paternal chromosome. In AS mouse model, inhibition of the UBE3A-ATS transcription can reactivate paternal UBE3A. To translate such an approach to humans, the development of a cellular model for this disease is necessary. Here we sought to develop cellular model systems of AS from patient-derived fibroblasts and evaluate their imprinting status using RNA FISH-based single-cell approaches. First, a neural direct conversion protocol based on expression of two neuronal transcription factors - ASCL1, NGN2 – and SMAD pathway inhibitors was tried in order to convert fibroblasts into neurons. Despite high infection efficiency and detection of transgenic ASCL1 expression, the generated “iNs” did not show signs of neuronal identity based on RT-qPCR and IF analysis. This failure might have been caused by lack of lentiviruses concentration by ultracentrifugation, antibiotic selection skipping and/or dislodging of the cells under conversion. Second, we tried to generate NPCs from iPSCs using a commercially available differentiation protocol. Based on RT-qPCR and IF analysis, the generated “NPCs” failed to express the correct genetic markers. This failure might be explained by inappropriate accelerated division rate of the cells during induction or lack of pluripotency of the newly-generated iPSCs used. Despite unsuccessful generation of neuronal cells, we were able to optimize nascent-transcript RNA FISH, combining UBE3A and paternally expressed SNORD116, which is a crucial tool to confirm the imprinting status of the Angelman locus in newly-generated cells. With future efforts, the establishment of AS cellular model systems will serve as drug screening platform to test paternal UBE3A reactivation as a therapeutic target for AS. Advisors/Committee Members: Rocha, Simão.

Subjects/Keywords: Angelman Syndrome; disease modelling; UBE3A; UBE3A-ATS; neural direct conversion; iPSCs neural differentiation; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

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APA (6^th Edition):

Joaquim, M. I. L. (2017). Exploring cell reprogramming techniques for Angelman Syndrome disease modelling. (Thesis). Universidade Nova. Retrieved from https://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/42365

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Joaquim, Mariana Isabel Lopes. “Exploring cell reprogramming techniques for Angelman Syndrome disease modelling.” 2017. Thesis, Universidade Nova. Accessed March 08, 2021. https://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/42365.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Joaquim, Mariana Isabel Lopes. “Exploring cell reprogramming techniques for Angelman Syndrome disease modelling.” 2017. Web. 08 Mar 2021.

Vancouver:

Joaquim MIL. Exploring cell reprogramming techniques for Angelman Syndrome disease modelling. [Internet] [Thesis]. Universidade Nova; 2017. [cited 2021 Mar 08]. Available from: https://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/42365.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Joaquim MIL. Exploring cell reprogramming techniques for Angelman Syndrome disease modelling. [Thesis]. Universidade Nova; 2017. Available from: https://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/42365

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

McMaster University

9. Beshara, Simon P. PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX.

Degree: PhD, 2016, McMaster University

URL: http://hdl.handle.net/11375/20663

►

A holy grail in neuroscience is being able to control plasticity to facilitate recovery from insult in the adult brain. Despite success in animal models,… (more)

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A holy grail in neuroscience is being able to control plasticity to facilitate recovery from insult in the adult brain. Despite success in animal models, few therapies have translated from bench to bedside. This thesis is aimed at addressing 2 major stumbling blocks in translation. The first gap is in our understanding of the mechanisms of plasticity-enhancing therapies, and the second is in our understanding the relevance of those mechanisms for human development. In chapters 2 and 3, I address the first gap by asking whether fluoxetine, a selective serotonin reuptake inhibitor, which reinstates juvenile-like plasticity in adult animals, reinstates a juvenile-like synaptic environment. We found evidence to suggest that fluoxetine is neuroprotective, as it rescued all of the MD-driven changes, but surprisingly we found no evidence that fluoxetine recreated a juvenile-like synaptic environment, with the exception of Ube3A. Ube3A is necessary for critical period plasticity, indicating that Ube3A may play a crucial in enhancing plasticity in the adult cortex. In chapter 4, I address whether D-serine, an amino acid that has similar effects to fluoxetine in terms of both plasticity and anti-depression, shares a common neurobiological signature with fluoxetine. I found that D-serine’s effects were strikingly similar to fluoxetine, with respect to markers of the E/I balance, indicating that it may be an effective alternative to fluoxetine. In chapter 5, I address the second gap by studying the development of 5 glutamatergic proteins in human V1. Some changes occurred early, as would be predicted from animals studies, while other changes were protracted, lasting into the 4th decade. These results will help guide the use of treatments, like fluoxetine, which effect glutamatergic proteins. iv Together the findings in this thesis significantly advances our understanding of the mechanisms involved in restating plasticity in the adult cortex, and their relevance to humans.

Dissertation

Doctor of Philosophy (PhD)

Neurons change to rewire, adapt, and recover. This plasticity is greatest early in development, so much research has focused on bringing it back in adults. There has been amazing progress in animal models, but this has not translated to humans. Two reasons for this are that we do not fully understand the mechanisms of these treatments in animals or whether those mechanisms are relevant for humans. My thesis addresses this by studying how 2 treatments, fluoxetine and D-serine, affect proteins that are important for plasticity, and how those proteins develop in the humans. I found that these treatments are neuroprotective, but do not recreate a younger state. One interesting standout is an increase in Ube3A, which is essential for juvenile plasticity. I also found that much of human development is similar to animals, but the time course for some proteins is uniquely prolonged in humans. These findings have implications for the use of plasticity-enhancing treatments at different ages.

Advisors/Committee Members: Murphy, Kathryn, Neuroscience.

Subjects/Keywords: plasticity; NMDA; AMPA; glutamate; GABA; metaplasticity; Human development; fluoxetine; D-serine; Ube3A; PSD-95; silent synapses; visual cortex; vision; amblyopia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Beshara, S. P. (2016). PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/20663

Chicago Manual of Style (16^th Edition):

Beshara, Simon P. “PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX.” 2016. Doctoral Dissertation, McMaster University. Accessed March 08, 2021. http://hdl.handle.net/11375/20663.

MLA Handbook (7^th Edition):

Beshara, Simon P. “PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX.” 2016. Web. 08 Mar 2021.

Vancouver:

Beshara SP. PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX. [Internet] [Doctoral dissertation]. McMaster University; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/11375/20663.

Council of Science Editors:

Beshara SP. PLASTICITY MECHANISMS IN VISUAL CORTEX: ANIMAL MODELS AND HUMAN CORTEX. [Doctoral Dissertation]. McMaster University; 2016. Available from: http://hdl.handle.net/11375/20663

University of Debrecen

10. Konyhás, Nóra. Az UBE3A gén vizsgálata Angelman szindrómában .

Degree: DE – Általános Orvostudományi Kar, University of Debrecen

URL: http://hdl.handle.net/2437/214566

► Az Angelman szindróma egy neurogenetikai megbetegedés, melynek fő tünetei a szellemi és motoros fejlődés késése, beszédzavar, alvászavarok, epilepsziás rohamok, mentális retardáció és állandó nevetési kényszer.… (more)

Subjects/Keywords: Angelman szindróma; UBE3A gén; Sanger szekvenálás; 1-10 exon

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Konyhás, N. (n.d.). Az UBE3A gén vizsgálata Angelman szindrómában . (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/214566

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Konyhás, Nóra. “Az UBE3A gén vizsgálata Angelman szindrómában .” Thesis, University of Debrecen. Accessed March 08, 2021. http://hdl.handle.net/2437/214566.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Konyhás, Nóra. “Az UBE3A gén vizsgálata Angelman szindrómában .” Web. 08 Mar 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Konyhás N. Az UBE3A gén vizsgálata Angelman szindrómában . [Internet] [Thesis]. University of Debrecen; [cited 2021 Mar 08]. Available from: http://hdl.handle.net/2437/214566.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

Konyhás N. Az UBE3A gén vizsgálata Angelman szindrómában . [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/214566

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

11. YUAN QIANG. MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS.

Degree: 2019, National University of Singapore

URL: https://scholarbank.nus.edu.sg/handle/10635/154974

Subjects/Keywords: Angelman syndrome; BK channel; UBE3A; human neurons; organoid; synchronization

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

QIANG, Y. (2019). MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS. (Thesis). National University of Singapore. Retrieved from https://scholarbank.nus.edu.sg/handle/10635/154974

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

QIANG, YUAN. “MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS.” 2019. Thesis, National University of Singapore. Accessed March 08, 2021. https://scholarbank.nus.edu.sg/handle/10635/154974.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

QIANG, YUAN. “MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS.” 2019. Web. 08 Mar 2021.

Vancouver:

QIANG Y. MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS. [Internet] [Thesis]. National University of Singapore; 2019. [cited 2021 Mar 08]. Available from: https://scholarbank.nus.edu.sg/handle/10635/154974.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

QIANG Y. MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS. [Thesis]. National University of Singapore; 2019. Available from: https://scholarbank.nus.edu.sg/handle/10635/154974

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

12. Tzagkaraki, Evmorfia. Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου.

Degree: 2013, University of Crete (UOC); Πανεπιστήμιο Κρήτης

URL: http://hdl.handle.net/10442/hedi/38015

►

Angelman Syndrome is a neurodevelopmental disorder with a complex phenotype caused by deficiency of maternal UBE3A gene expression on the imprinted Prader Willi/ Angelman syndrome… (more)

▼

Angelman Syndrome is a neurodevelopmental disorder with a complex phenotype caused by deficiency of maternal UBE3A gene expression on the imprinted Prader Willi/ Angelman syndrome critical region which results from chromosomal deletions, uniparental disomy and imprinting defects of the 15q11-q13 region in 70- 80% of patients. Loss of function mutations in maternally inherited UBE3A is the genetic cause of the disease in 5- 10% of patients. In the present study, molecular analysis of the UBE3A gene in 43 Greek Angelman syndrome patients revealed two pathological mutations- one of them novel - and four sequence changes considered as polymorphic variants- one of them novel alteration. The two pathological mutations were revealed in patients with typical electroencephalography pattern and microcephaly. ECMA assay (Enzymatic Cleavage Mismatch Analysis) has been applied for the first time as a screening method for molecular analysis of UBE3A gene and it has been evaluated for its sensitivity and reliability.Although the number of UBE3A mutations reported in the literature is increasing, mental retardation phenotypes are complex, suggesting additional mutation analysis of other genes (e.g. MECP2 and CDKL5), or genome wide screening methods (such as array- CGH), especially in atypical cases.

Το Σύνδρομο Angelman είναι μία νευροαναπτυξιακή διαταραχή η οποία εκδηλώνεται με ποικίλα φαινοτυπικά χαρακτηριστικά, προκαλείται από την ελαττωματική έκφραση του γονιδίου UBE3A από το μητρικό αλληλόμορφο και οφείλεται κυρίως σε χρωμοσωμικά ελλείμματα, πατρική μονογονεϊκή δισωμία και βλάβη στο κέντρο γονιδιακής αποτύπωσης της περιοχής 15q11- q13. Οι τρεις παραπάνω παθογενετικοί μηχανισμοί ανιχνεύονται στο 70- 80% των ασθενών με σύνδρομο Angelman. Σημειακές μεταλλάξεις στο μητρικό αλληλόμορφο του γονιδίου UBE3A έχουν ανιχνευθεί και αποτελούν την γενετική βάση του συνδρόμου σε ποσοστό 5- 10% των ασθενών.Στην παρούσα μελέτη, πραγματοποιήθηκε μοριακή ανάλυση του γονιδίου UBE3A σε συνολικά 53 ασθενείς με κλινικά χαρακτηριστικά συνδρόμου Angelman. Ανιχνεύθηκαν δύο παθολογικές σημειακές μεταλλάξεις, η μία εκ των οποίων αναφέρεται για πρώτη φορά στην διεθνή βιβλιογραφία, και τέσσερις πολυμορφικές αλλαγές, συμπεριλαμβανομένου και μίας πρωτότυπης. Και οι δύο ασθενείς στους οποίους ανιχνεύθηκαν σημειακές μεταλλάξεις, έφεραν τυπικό παθολογικό ηλεκτροεγκεφαλογράφημα και μικροκεφαλία. Στην μία εκ των δύο οικογενειών ακολούθησε προγεννητικός έλεγχος σε δύο επόμενες κυήσεις, όπου σε καμμία από τις δύο δεν ανιχνεύθηκε η παθολογική μετάλλαξη.Για πρώτη φορά χρησιμοποιήθηκε η μέθοδος ECMA (Enzymatic Cleavage Mismatch Analysis) για την μοριακή ανάλυση του γονιδίου UBE3A σε ασθενείς με κλινικά χαρακτηριστικά συνδρόμου Angelman, και αξιολογήθηκε η ακρίβεια, η ευαισθησία και η επαναληψιμότητά της.Παρόλο που η ανίχνευση σημειακών μεταλλάξεων στο γονίδιο UBE3A συνεχώς αυξάνεται, η μεγάλη ετερογένεια των ασθενών με διανοητική και αναπτυξιακή καθυστέρηση που παραπέμπονται για διερεύνηση συνδρόμου Angelman, καθιστά πολλές φορές αναγκαία την μοριακή ανάλυση και…

Subjects/Keywords: Σύνδρομο Angelman; Ube3a γονίδιο; Μεταλλάξεις; Ηλεκτροεγκεφαλογράφημα; Μέθοδος ecma (enzymatic cleavage mismatch analysis; Ανάλυση της πρωτοταγούς δομής του DNA; Angelman syndrome; Ube3a gene; Mutations; Eeg electroencephalography; Ecma assay (enzymatic cleavage mismatch analysis; Sequencing analysis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tzagkaraki, E. (2013). Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου. (Thesis). University of Crete (UOC); Πανεπιστήμιο Κρήτης. Retrieved from http://hdl.handle.net/10442/hedi/38015

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tzagkaraki, Evmorfia. “Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου.” 2013. Thesis, University of Crete (UOC); Πανεπιστήμιο Κρήτης. Accessed March 08, 2021. http://hdl.handle.net/10442/hedi/38015.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tzagkaraki, Evmorfia. “Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου.” 2013. Web. 08 Mar 2021.

Vancouver:

Tzagkaraki E. Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου. [Internet] [Thesis]. University of Crete (UOC); Πανεπιστήμιο Κρήτης; 2013. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/10442/hedi/38015.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tzagkaraki E. Μοριακή μελέτη ασθενών με σύνδρομο Angelman: συσχέτιση φαινότυπου - γονότυπου. [Thesis]. University of Crete (UOC); Πανεπιστήμιο Κρήτης; 2013. Available from: http://hdl.handle.net/10442/hedi/38015

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Vanderbilt University

13. Delahanty, Ryan James. Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism.

Degree: PhD, Human Genetics, 2010, Vanderbilt University

URL: http://hdl.handle.net/1803/10492

► TOWARD AN UNDERSTANDING OF THE ROLE OF CHROMOSOME 15Q11-Q13 IN IDIOPATHIC AUTISM RYAN JAMES DELAHANTY Dissertation under the direction of Dr. James S. Sutcliffe The… (more)

▼ TOWARD AN UNDERSTANDING OF THE ROLE OF CHROMOSOME 15Q11-Q13 IN IDIOPATHIC AUTISM RYAN JAMES DELAHANTY Dissertation under the direction of Dr. James S. Sutcliffe The 15q11-q13 region is a genomic interval involved in a growing number of genomic disorders. The genes in the interval are subject to imprinting and parent-of-origin expression effects. Maternal duplication of the 15q11-q13 region is the most frequent chromosomal abnormality associated with autism. Extensive work has indicated that two genes in this interval, UBE3A and GABRB3, show very strong evidence for association with autism. To examine the extent to which these genes may contribute to autism, family-based association studies of UBE3A and GABRB3 were undertaken. Here we have investigated the role of common variants of UBE3A and GABRB3 in autism as well as the an intense investigation of the association of a rare variant, P11S in GABRB3 and its role in autism. In addition, we have investigated MECP2, a gene which when defective causes Rett syndrome, and potentially regulates gene expression of UBE3A and GABRB3. e have used genetic and biochemical methods to investigate two genes in the UBE3A network, ECT2 and GCH1. Finally, we used genotype data and multiplex ligation probe amplification (MLPA) to determine if copy number variation in the form of deletions and duplications in UBE3A and GABRB3 may play a role in the etiology of autism. Our findings indicated that a common allele of MECP2 is associated with autism, which was replicated by another group. We show association with UBE3A and its associated genes ECT2 and GCH1 as well as a relationship between UBE3A and GCH1 gene and protein expression, observed in a model system, and validated in our samples, which may provide guidance and support for a role of UBE3A and its action at the synapse and potential contribution to autism. We show modest association of GABRB3 with autism and epilepsy, but find a single coding variant, P11S, maternally overtransmitted and in such cases dramatically increasing autism risk. Finally, we found little evidence for microdeletions or microduplications in UBE3A and GABRB3 to contribute to autism pathology. The work presented in this thesis expands on earlier findings with regard to the role of GABRB3 and UBE3A in autism and represents an investigation of variants in these and their related genes spanning the spectrum from common variants of modest effect to rare variants of more profound effect. The availability of new technologies to evaluate copy number variation and next generation sequencing will likely uncover a wider role for 15q11-q13 and related loci in autism. The role of more highly penetrant private mutations of this nature is suggested as an avenue for further investigation. Advisors/Committee Members: Lawrence T. Reiter (committee member), John A. Phillips III (committee member), Chun Li (committee member), James Sutcliffe (committee member), Scott Williams (Committee Chair).

Subjects/Keywords: 15q11-q13; association; autism; GABRB3; UBE3A; ECT2; GCH1; CNV; MECP2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Delahanty, R. J. (2010). Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10492

Chicago Manual of Style (16^th Edition):

Delahanty, Ryan James. “Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed March 08, 2021. http://hdl.handle.net/1803/10492.

MLA Handbook (7^th Edition):

Delahanty, Ryan James. “Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism.” 2010. Web. 08 Mar 2021.

Vancouver:

Delahanty RJ. Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1803/10492.

Council of Science Editors:

Delahanty RJ. Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/10492

14. Filonova, Irina. Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome.

Degree: 2014, University of South Florida

URL: https://scholarcommons.usf.edu/etd/5015

► Angelman Syndrome (AS) is a severe neurodevelopmental disorder that affects 1:12000 newborns. It is characterized by mental retardation, delayed major motor and cognitive milestones, seizures,… (more)

▼ Angelman Syndrome (AS) is a severe neurodevelopmental disorder that affects 1:12000 newborns. It is characterized by mental retardation, delayed major motor and cognitive milestones, seizures, absence of speech and excessive laughter. The majority of AS cases arise from deletions or mutations of UBE3A gene located on the chromosome 15q11-13. UBE3A codes for E3-ubiquitin ligase that target specific proteins for degradation. To date, a wide variety of Ube3a substrates has been identified. The accumulation of Ube3a-dependent proteins and their effect on the multitude of signal transduction pathways are` considered the main cause of the AS pathology. While the majority of research has been directed towards target identifications, the overall role of Ube3a in activity-dependent synaptic plasticity has been greatly overlooked. The present work is designed to fill some of these knowledge gaps. Chapter 2 is focused on the activity-dependent aspect of Ube3a expression following neuronal stimulation in vivo and in vitro. We examined total Ube3a expression followed by KCl depolarization in neuronal primary culture. By utilizing a subcellular fractionation technique, we were able to determine which cellular pools are responsive to the depolarization. Next, a fear conditioning paradigm (FC) was used to activate neurons in the paternal Ube3a-YFP reporter mouse brain. This mouse model allowed us to resolve spatial and temporal alterations of the maternal and the paternal Ube3a in hippocampus and cortex followed by FC. In accordance to KCl depolarization results, we observed alterations in Ube3a protein but at later time points. Furthermore, we investigated if the absence of activity-dependent Ube3a changes has any effect on learning and memory kinase activation. We utilized KCl and FC to determine synaptic activity-induced ERK 1/2 phosphorylation in acute hippocampal slices and in CA1 area of hippocampus of wild type (Ube3a m+/p+) and Ube3a deficient mice (Ube3a m-/p+). We demonstrated that Ube3a loss leads to impaired activity-dependent ERK 1/2 phosphorylation. It has been established that Ube3a m-/p+ mice have a profound deficit in LTP, implying the importance of this ligase in excitatory synaptic transmission. The abnormal LTP could be partially explained by an aberrant CaMKII function, decreased activity-dependent ERK 1/2 phosphorylation and reduced phosphatase activity. These proteins have also been implicated in another form of synaptic plasticity such as long-term depression (LTD). Chapter 3, we investigated the contribution of Ube3a to NMDAR - dependent and - independent LTD. Our data showed that Ube3a m-/p+ P21-30 animals exhibit the impairments in both forms of LTD. Next, we focused on elucidating molecular mechanism underlying the reduced mGluR1/5-LTD. We discovered that mGluR1/5 kinase activation such as ERK, mTOR and p38 is not affected by Ube3a loss. In concordance with previous work, we detected increased Arc expression together with abnormal AMPAR distribution in the Ube3a m-/p+ hippocampus. Surprisingly, the…

Subjects/Keywords: Angelman Syndrome; ERK phosphorylation; Fragile X Retardation; LTD; Ube3a; Molecular Biology; Neurosciences

…Figure 4.2 Synaptic Ube3a expression is upregulated in response to mGluR1/5 stimulation… …in wild type but not in Fmr1 KO animals. 106 Figure 4.3 The increase in Ube3a expression… …exogenous Ube3a to hippocampus of Fmr1 KO mice didn‘t influence the locomotor behavior. 108… …Figure 4.5 The associative but not spatial memory is affected by the increased Ube3a expression… …social interaction or marble burying tests. 110 Figure 4.7 Ube3a-AAV expression in Ube3a m-/p…

12 more images…

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APA (6^th Edition):

Filonova, I. (2014). Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome. (Thesis). University of South Florida. Retrieved from https://scholarcommons.usf.edu/etd/5015

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Filonova, Irina. “Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome.” 2014. Thesis, University of South Florida. Accessed March 08, 2021. https://scholarcommons.usf.edu/etd/5015.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Filonova, Irina. “Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome.” 2014. Web. 08 Mar 2021.

Vancouver:

Filonova I. Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome. [Internet] [Thesis]. University of South Florida; 2014. [cited 2021 Mar 08]. Available from: https://scholarcommons.usf.edu/etd/5015.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Filonova I. Ube3a Role in Synaptic Plasticity and Neurodevelopmental Disorders.The Lessons from Angelman Syndrome. [Thesis]. University of South Florida; 2014. Available from: https://scholarcommons.usf.edu/etd/5015

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. Bruinsma, Caroline. The Role of UBE2A and UBE3A in Motor- and Cognitive Function.

Degree: 2016, Erasmus University Medical Center

URL: http://hdl.handle.net/1765/80157

Subjects/Keywords: Ubiquitin Proteasome pathway; UBE2A protein; UBE3A protein; UBE2A deficiency syndrome; X-linked intellectual disability type Nascimento; Angelman syndrome (AS)

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APA (6^th Edition):

Bruinsma, C. (2016). The Role of UBE2A and UBE3A in Motor- and Cognitive Function. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/80157

Chicago Manual of Style (16^th Edition):

Bruinsma, Caroline. “The Role of UBE2A and UBE3A in Motor- and Cognitive Function.” 2016. Doctoral Dissertation, Erasmus University Medical Center. Accessed March 08, 2021. http://hdl.handle.net/1765/80157.

MLA Handbook (7^th Edition):

Bruinsma, Caroline. “The Role of UBE2A and UBE3A in Motor- and Cognitive Function.” 2016. Web. 08 Mar 2021.

Vancouver:

Bruinsma C. The Role of UBE2A and UBE3A in Motor- and Cognitive Function. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1765/80157.

Council of Science Editors:

Bruinsma C. The Role of UBE2A and UBE3A in Motor- and Cognitive Function. [Doctoral Dissertation]. Erasmus University Medical Center; 2016. Available from: http://hdl.handle.net/1765/80157

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