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Molecular and biophysical characterization of the glycinergic inhibitory system. / Seo-Kyung Chung

Swansea University Author: Seo-Kyung Chung

Abstract

Glycinergic neurotransmission is a major inhibitory influence in the CNS and defects are associated with paroxysmal neuromotor disorder, hyperekplexia with mutations in subunits of the inhibitory glycine receptor which facilitates postsynaptic ligand-binding, ion-channels. This study investigates th...

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Published: 2009
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42277
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first_indexed 2018-08-02T18:54:19Z
last_indexed 2019-10-21T16:47:31Z
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spelling 2018-08-29T14:34:31.8907172 v2 42277 2018-08-02 Molecular and biophysical characterization of the glycinergic inhibitory system. 18ab4933731959cbd9f014accf7d3373 NULL Seo-Kyung Chung Seo-Kyung Chung true true 2018-08-02 Glycinergic neurotransmission is a major inhibitory influence in the CNS and defects are associated with paroxysmal neuromotor disorder, hyperekplexia with mutations in subunits of the inhibitory glycine receptor which facilitates postsynaptic ligand-binding, ion-channels. This study investigates the human glycinergic system by; 1) Mutation analysis of glycinergic candidate genes in hyperekplexia: the DNA sequencing of GLRAl in 88 hyperekplexia patients revealed 30 sequence variants; 21 were inherited in recessive mode or part of compound heterozygosity, indicating that recessive hyperekplexia is more common than previously expected. Further screening of the glycine transporter-2 gene (SLC6A5) as a candidate gene, 12 SLC6A5 mutations were found in 7 human hyperekplexia cases inherited predominantly by compound heterozygosity. 2) Biophysical analysis and molecular modelling of GLRAl mutations: which demonstrated that subcellular localisation defects were the major mechanism underlying recessive mutations. Other mutants typically show alterations in the dose-response curve for glycine suggestive of disrupted signal transduction. This study reports the first hyperekplexia mutation associated with leaky current suggesting tonic channel opening as a new receptor mechanism and fully-supported by molecular modelling. 3) Molecular and immunoreactive analysis of gephyrin heterogeneity in human brain: gephyrin encodes a multifunctional cytoplasmic protein important for organizing glycine and GABAa receptors at the postsynaptic membrane. Gephyrin has many different transcript isoforms and the study describes the population / distribution of gephyrin isoforms in neuronal tissues using molecular and immunohistochemical techniques. The heterogeneity of gephyrin cassettes indicates that each cassette is temporally and spatially regulated with unique patterns of glycine receptors co-localisation and we hypothesise that different gephyrin isoforms exhibit differential binding specificity affecting protein-protein interactions. This thesis describes that hyperekplexia is definitively a glycinergic disorder with several mechanism of molecular pathogenicity. Moreover, the underlying complexity of proteins, such as gephyrin, reveals further challenges in interpretating the functional significance of the neuronal heterogeneity. E-Thesis Neurosciences.;Biophysics. 31 12 2009 2009-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T14:34:31.8907172 2018-08-02T16:24:28.6669869 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Seo-Kyung Chung NULL 1 0042277-02082018162441.pdf 10797985.pdf 2018-08-02T16:24:41.8030000 Output 11587475 application/pdf E-Thesis true 2018-08-02T16:24:41.8030000 false
title Molecular and biophysical characterization of the glycinergic inhibitory system.
spellingShingle Molecular and biophysical characterization of the glycinergic inhibitory system.
Seo-Kyung Chung
title_short Molecular and biophysical characterization of the glycinergic inhibitory system.
title_full Molecular and biophysical characterization of the glycinergic inhibitory system.
title_fullStr Molecular and biophysical characterization of the glycinergic inhibitory system.
title_full_unstemmed Molecular and biophysical characterization of the glycinergic inhibitory system.
title_sort Molecular and biophysical characterization of the glycinergic inhibitory system.
author_id_str_mv 18ab4933731959cbd9f014accf7d3373
author_id_fullname_str_mv 18ab4933731959cbd9f014accf7d3373_***_Seo-Kyung Chung
author Seo-Kyung Chung
author2 Seo-Kyung Chung
format E-Thesis
publishDate 2009
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Glycinergic neurotransmission is a major inhibitory influence in the CNS and defects are associated with paroxysmal neuromotor disorder, hyperekplexia with mutations in subunits of the inhibitory glycine receptor which facilitates postsynaptic ligand-binding, ion-channels. This study investigates the human glycinergic system by; 1) Mutation analysis of glycinergic candidate genes in hyperekplexia: the DNA sequencing of GLRAl in 88 hyperekplexia patients revealed 30 sequence variants; 21 were inherited in recessive mode or part of compound heterozygosity, indicating that recessive hyperekplexia is more common than previously expected. Further screening of the glycine transporter-2 gene (SLC6A5) as a candidate gene, 12 SLC6A5 mutations were found in 7 human hyperekplexia cases inherited predominantly by compound heterozygosity. 2) Biophysical analysis and molecular modelling of GLRAl mutations: which demonstrated that subcellular localisation defects were the major mechanism underlying recessive mutations. Other mutants typically show alterations in the dose-response curve for glycine suggestive of disrupted signal transduction. This study reports the first hyperekplexia mutation associated with leaky current suggesting tonic channel opening as a new receptor mechanism and fully-supported by molecular modelling. 3) Molecular and immunoreactive analysis of gephyrin heterogeneity in human brain: gephyrin encodes a multifunctional cytoplasmic protein important for organizing glycine and GABAa receptors at the postsynaptic membrane. Gephyrin has many different transcript isoforms and the study describes the population / distribution of gephyrin isoforms in neuronal tissues using molecular and immunohistochemical techniques. The heterogeneity of gephyrin cassettes indicates that each cassette is temporally and spatially regulated with unique patterns of glycine receptors co-localisation and we hypothesise that different gephyrin isoforms exhibit differential binding specificity affecting protein-protein interactions. This thesis describes that hyperekplexia is definitively a glycinergic disorder with several mechanism of molecular pathogenicity. Moreover, the underlying complexity of proteins, such as gephyrin, reveals further challenges in interpretating the functional significance of the neuronal heterogeneity.
published_date 2009-12-31T03:52:39Z
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score 11.012857

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