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You searched for subject:(15q11 q13). Showing records 1 – 3 of 3 total matches.

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Texas A&M University

1. Benjamin, Jade Marie. Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention.

Degree: PhD, Genetics, 2017, Texas A&M University

Human chromosome 15q11-q13 contains a cluster of imprinted genes that are associated with a number of neurological disorders that exhibit non-Mendelian patterns of inheritance, such as Angelman syndrome (AS) and Prader-Willi syndrome. Angelman syndrome is caused by the loss-of-expression of maternally inherited ubiquitin E3A protein ligase gene (UBE3A). Prader-Willi syndrome is caused by loss-of-function of paternally inherited SNORD116 snoRNAs (small nucleolar RNAs), which are expressed as part of a long polycistronic transcriptional unit (PTU) comprised of SNURF-SNRPN, additional orphan C/D box snoRNA clusters, and the UBE3A antisense transcript (UBE3A-AS). The full-length transcript of PTU, including UBE3A-AS, is only expressed in neurons causing the imprinting of paternal UBE3A. Why this occurs in only neurons remains largely unknown. Furthermore, this neuron-specific imprinting adds additional difficulty for therapeutic intervention. In this dissertation, the imprinting mechanism of UBE3A is examined in detail, while an alternative high-throughput screening (HTS) method for drug discovery in neurons is developed. A combination of bioinformatic and molecular analysis of the human and mouse PTU revealed that UBE3A-AS/Ube3a-AS is extensively processed via 5’ capping 3’polyadenyation and alternative splicing, suggesting that the antisense may have regulatory functions apart from imprinting UBE3A in neurons. Following this discovery, the transcriptional profiles and processing of mouse paternal Ube3a was investigated as literature suggested that imprinted paternal Ube3a, unlike other imprinted genes, was transcribed up to intron 4. This analysis unveiled a fourth Ube3a isoform that terminates within intron 4. Moreover, expression of this isoform correlated with Ube3a-AS expression, suggesting alternative reasons for the imprinting of Ube3a. In addition to the analysis of the imprinting of Ube3a, an alternative solution for drug discovery for central nervous system disorders was developed and validated. Here, an embryonic stem cell-derived neuronal culture system was developed for HTS and tested using the paternal Ube3a^Y FP reporter cell-line. Using a known reactivator of paternal Ube3a, Topotecan - a topoisomerase inhibitor, as a positive control a proof-of-concept study demonstrated the utility of this method for HTS drug discovery. Collectively, these results advance the field and understanding of antisense lncRNAs and provide a versatile tool for drug discovery for neurological disorders. Advisors/Committee Members: Dindot, Scott V (advisor), Segal, David J (committee member), Threadgill, David W (committee member), Welsh, C. Jane (committee member).

Subjects/Keywords: Angelman syndrome; 15q11-q13; neurodevelopmental disorders; bioinformatics; HTS

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

APA (6th Edition):

Benjamin, J. M. (2017). Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/187202

Chicago Manual of Style (16th Edition):

Benjamin, Jade Marie. “Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention.” 2017. Doctoral Dissertation, Texas A&M University. Accessed March 08, 2021. http://hdl.handle.net/1969.1/187202.

MLA Handbook (7th Edition):

Benjamin, Jade Marie. “Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention.” 2017. Web. 08 Mar 2021.

Vancouver:

Benjamin JM. Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention. [Internet] [Doctoral dissertation]. Texas A&M University; 2017. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1969.1/187202.

Council of Science Editors:

Benjamin JM. Understanding the Imprinting Mechanism of UBE3A for Therapeutic Intervention. [Doctoral Dissertation]. Texas A&M University; 2017. Available from: http://hdl.handle.net/1969.1/187202


Vanderbilt University

2. McCauley, Jacob Lee. Genetic and phenotypic dissection of autism susceptibility.

Degree: PhD, Molecular Physiology and Biophysics, 2005, Vanderbilt University

Autism is a severe neurodevelopmental disorder characterized by deficits in language and social interaction, and patterns of repetitive and stereotyped behaviors, interests and activities. Evidence indicates that autism has a predominantly genetic etiology, and that as many as fifteen genes may contribute to disease susceptibility. One model suggests autism may result from oligogenic inheritance, with locus heterogeneity, such that different families or individuals possess a different mix of susceptibility alleles. In this dissertation, I present genome-wide linkage studies of autism and traits comprising the aspects of the broader phenotype to identify autism susceptibility loci. I further document detailed molecular and genetic analyses of candidate genes in regions detected by linkage, and in the case of 15q11-q13, as chromosomal duplications found in 1-3% of autism cases. A unifying theme to my dissertation is the focus of genetic studies on genes acting within candidate neurobiological systems suspected of involvement in autism. Genetic analyses include linkage, linkage refinement, construction of detailed linkage disequilibrium (LD) and corresponding haplotype maps across candidate loci, and tests for transmission disequilibrium of single markers and haplotypes. Molecular studies of select candidates aim to identify functional variation on associated alleles; in the absence of association they seek to identify potential rare disease-related variants considering for example evolutionarily conserved sequence. I hypothesize that there are allelic variants, which underlie genetic linkage and/or association to autism and related traits, and these contribute to autism susceptibility through both direct and interactive effects. The goal of this study is to dissect the genetic etiology of autism by leveraging trait-based phenotypic subsets of autism using the approaches and tools I have outlined here. Advisors/Committee Members: Randy D. Blakely (committee member), Scott M. Williams (committee member), Jason H. Moore (committee member), Doug P. Mortlock (committee member), James S. Sutcliffe (committee member), Jonathan L. Haines (Committee Chair).

Subjects/Keywords: linkage; serotonin; GABA; chromosome 17; chromosome 19; chromosome 15q11-q13; association; autism; genetics

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

APA (6th Edition):

McCauley, J. L. (2005). Genetic and phenotypic dissection of autism susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10664

Chicago Manual of Style (16th Edition):

McCauley, Jacob Lee. “Genetic and phenotypic dissection of autism susceptibility.” 2005. Doctoral Dissertation, Vanderbilt University. Accessed March 08, 2021. http://hdl.handle.net/1803/10664.

MLA Handbook (7th Edition):

McCauley, Jacob Lee. “Genetic and phenotypic dissection of autism susceptibility.” 2005. Web. 08 Mar 2021.

Vancouver:

McCauley JL. Genetic and phenotypic dissection of autism susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2005. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1803/10664.

Council of Science Editors:

McCauley JL. Genetic and phenotypic dissection of autism susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2005. Available from: http://hdl.handle.net/1803/10664


Vanderbilt University

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

Degree: PhD, Human Genetics, 2010, Vanderbilt University

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 (6th 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 (16th 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 (7th 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

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