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研究生:沈裕智
研究生(外文):Yu-Chih Shen
論文名稱:穀氨酸鹽訊號傳遞以及突觸可塑性相關基因在精神分裂症致病機轉上之遺傳及功能性研究
論文名稱(外文):The genetic and functional study of some candidate genes involved in glutamatergic neurotransmission and synaptic plasticity in schizophrenia
指導教授:陳嘉祥陳嘉祥引用關係
指導教授(外文):Chia-Hsiang Chen
學位類別:博士
校院名稱:慈濟大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:117
中文關鍵詞:精神分裂症稀有變異穀氨酸鹽訊息傳遞路徑突觸可塑性GRIN3AVGLUT1VGLUT2SYPGAP-43NRGN
外文關鍵詞:SYPVGLUT2VGLUT1GRIN3Aglutamate neurotransmissionrare variantssynaptic plasticityschizophreniaGAP-43NRGN
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精神分裂症是一種慢性、複雜、多基因遺傳的疾病,症狀以幻覺、妄想及思考障礙為主。若不治療常會合併語無倫次與行為異常,病因到現在為止並不完全清楚。有學者推測腦中穀氨酸鹽(glutamate)的訊號傳遞路徑以及突觸可塑性(synaptic plasticity)異常可能與精神分裂症的病理有關。假設調控穀氨酸鹽釋放或接收的一些分子元件(如GRIN3A, VGLUT1, VGLUT2)或是與突觸可塑性相關的一些分子元件(如SYP, GAP-43, NRGN)產生基因變異,可能讓穀氨酸鹽的訊號傳遞失調或突觸可塑性異常而產生臨床症狀。本研究希望可以釐清這幾個分子的基因變異與精神分裂症病理的相關性。我們在台灣收集了約三百個精神分裂症病人及三百個正常控制組個案。利用重定序(resequencing)的方式將病人組及控制組基因中與信使RNA(messengerRNA)轉錄有關的基因序列(包含啟動子區域)讀出並比對其差異。序列比對後將這幾個分子中常見的單一核酸多型性(SNPs)進行關連性分析後並未發現病人組及控制組的分佈頻率有顯著差別。然而,在病人組當中,我們發現幾個稀有變異(rare variants)。這些稀有變異在控制組中並未發現,暗示其可能與疾病相關。進一步利用報導基因表現分析(reporter gene assay)或利用生物資訊網站分析證明這些稀有變異可能會影響這些分子元件的功能。這一系列的研究顯示這些稀有變異會對調控穀氨酸鹽釋放或接收的一些分子元件或是與突觸可塑性相關的一些分子元件功能產生影響,可能是部分精神分裂症的致病原因。
Schizophrenia is a highly heritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Dysregulation of glutamate neurotransmission and aberrant synaptic plasticity have been implicated in the pathogenesis of this illness. We investigate the involvement of some candidate genes related to either glutamatergic neurotransmission (GRIN3A, VGLUT1, and VGLUT2) or synaptic plasticity (SYP, GAP-43, and NRGN) in the susceptibility to schizophrenia. In our series of genetic studies, we used a resequencing strategy to search for genetic variants in each candidate gene in a sample of around 300 schizophrenic and 300 control subjects, and assessed their associations with schizophrenia. After resequencing these candidate genes, no common polymorphisms appeared to play a major role in conferring susceptibility to schizophrenia in our population. However, we identified some patient specific rare variants. Collectively, these rare variants are significantly over-represented in patient as compared to control group. In addition, the results of the reporter gene assay and software analysis demonstrated their influence on the function of the studied gene, suggesting they may contribute to the pathogenesis of schizophrenia. Our study leads support to the hypothesis of multiple rare variants in schizophrenia,and provides genetic clues to indicate the involvement of dysregulation of glutamate neurotransmission and aberrant synaptic plasticity in this disorder.
致 謝 I
中文摘要 III
Abstract IV
Table of Contents V
List of Tables VIII
List of Figures X

CHAPTER ONE
The background 1
1.1 Schizophrenic disorder 2
1.2 Genetic studies of schizophrenia 4
1.2.1 Chromosome studies of schizophrenia 4
1.2.2 Linkage studies of schizophrenia 4
1.2.3 Association studies of schizophrenia 5
1.2.4 CNV studies of schizophrenia 6
1.3 Resequencing candidate genes 7
1.4 Schizophrenia candidate genes related to glutamatergic neurotransmission 8
1.4.1 Glutamate receptor, ionotropic, N-methyl-D-aspartate 3A gene (GRIN3A) 8
1.4.2 Vesicular glutamate transporter 1 gene (VGLUT1) 9
1.4.3 Vesicular glutamate transporter 2 gene (VGLUT2) 10
1.5 Schizophrenia candidate genes related to synaptic plasticity 11
1.5.1 Synaptophysin gene (SYP) 11
1.5.2 GAP-43 gene (GAP-43) 12
1.5.3 Neurogranin gene (NRGN) 12

CHAPTER TWO
Materials and methods 14
2.1 Subjects 15
2.2 Resequence candidate genes 16
2.3 Genetic association analysis 17
2.4 Gene expression assay 18
2.5 In silico analysis 19

CHAPTER THREE
Resequencing of the GRIN3A gene reveals some rare genetic variants that may increase the genetic burden in schizophrenia 20
3.1 SNP identification and association study with schizophrenia 21
3.2 Detection of rare variants associated with schizophrenia 28
3.3 Discussion 30

CHAPTER FOUR
Resequencing of the VGLUT1 gene reveals some rare genetic variants that may increase the genetic burden in schizophrenia 32
4.1 SNP identification and association study with schizophrenia 33
4.2 Detection of rare variants associated with schizophrenia 37
4.3 Discussion 39

CHAPTER FIVE
Resequencing of the VGLUT2 gene reveals some rare genetic variants that may increase the genetic burden in schizophrenia 43
5.1 SNP identification and association study with schizophrenia 44
5.2 Detection of rare variants associated with schizophrenia 50
5.3 Discussion 52

CHAPTER SIX
Resequencing of the SYP gene reveals some rare genetic variants that may increase the genetic burden in schizophrenia 55
6.1 SNP identification and association study with schizophrenia 56
6.2 Detection of rare variants associated with schizophrenia 61
6.3 Discussion 63

CHAPTER SEVEN
Genetic and functional analysis of the GAP-43 gene in schizophrenia 66
7.1 SNP identification and association study with schizophrenia 67
7.2 Detection of rare variants associated with schizophrenia 75
7.3 Functional characterization of c.-258-4722G>T using reporter gene activity assay 77
7.4 Discussion 79

CHAPTER EIGHT
Genetic and functional analysis of the NRGN gene in schizophrenia 82
8.1 SNP identification and association study with schizophrenia 83
8.2 Detection of rare variants associated with schizophrenia 90
8.3 Functional analysis of identified rare variants using reporter gene activity assay 91
8.4 In silico analysis of identified rare variants 93
8.5 Discussion 95

CHAPTER NINE
Conclusion 98

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