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系統識別號 U0026-0812200915263141
論文名稱(中文) citrin缺陷的分子診斷與機制
論文名稱(英文) Citrin deficiency: molecular diagnosis and mechanism
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 97
學期 2
出版年 98
研究生(中文) 林靖婷
研究生(英文) Jing-Ting Lin
電子信箱 t3696404@mail.ncku.edu.tw
學號 t3696404
學位類別 碩士
語文別 英文
論文頁數 73頁
口試委員 指導教授-謝淑珠
口試委員-陳炯瑜
口試委員-林秀娟
口試委員-蕭廣仁
中文關鍵字 甘胺酸  精胺丁二酸合成酵素  瓜胺酸血症 
英文關鍵字 citrullinemia  ASS  glycine 
學科別分類
中文摘要 Citrin是由基因SLC25A13所轉譯成一種需鈣的粒線體溶質載體蛋白,並且在尿素循環、核苷酸和蛋白質合成中扮演角色。它負責將來自粒線體的天門冬胺酸送到細胞質,並且將細胞質內的谷胺酸運送到粒線體,同時將NADH還原物質(NADH reducing equivalents)送到粒線體。Citrin異常會造成成人型第II瓜胺酸血症(Adult-onset type II citrullinemia, CTLN2)和新生兒肝內膽汁淤積症(Neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD)兩種表現型。臨床上可見病人會有血液中NADH/NAD+比值上升和肝臟精胺丁二酸合成酵素(argininosuccinate synthetase)缺乏的現象。近來研究顯示這種遺傳疾病在亞洲的發生率很高,因此本研究發展高解析度分析熔解曲線分析方法(High resoluiton melting analysis)來掃描SLC25A13基因變異及評估其在台灣的帶原率;並進一步探討citrin缺陷所造成肝性精胺丁二酸合成酵素缺乏的機制以及給予甘胺酸是否可以減緩此酵素的下降。DNA收集來自正常人(n=384)、肝癌(n=28)和NICCD(n=7)病人,掃描位在SLC25A13基因上外顯子第六、九、十一、十六和十七以及部分內在子第六、十和十一的檢測。藉由西方墨點法和液相層析串聯式質譜儀分別檢測給予H2O2或menadione後Huh-7細胞中精胺丁二酸合成酵素表現以及代謝物濃度的變化。並經由乳酸鹽和丙酮酸的比率來評估NADH/NAD+。另外也利用電穿孔法將citirn基因的shRNA表現載體轉染到Huh-7細胞中。結果顯示SLC25A13 基因851del4變異是台灣最常見的變異占有2.1%的帶原率並且。而在正常人中所找到的SLC25A13變異占有1/32,並且找到Q159X和R553Q這兩種新的變異。氧化壓力的增加會降低Huh-7細胞中精胺丁二酸合成酵素的表現量。在給予0.5 mM H2O2後,下降的情形可以持續到12個小時之久。而menadione(超氧自由基)的給予會造成細胞 GSH/GSSG比率下降有著劑量與時間的相關性。而在轉染標的SLC25A13基因的shRNA在Huh-7細胞48小時後,citrin蛋白的表現有明顯下降的情形;同時,乳酸鹽和丙酮酸的比率相較對照組也有上升的現象。在事先給予Huh-7細胞5 mM甘胺酸6小時或是10 mM甘胺酸4小時都可降低menadione所造成精胺丁二酸合成酵素下降的表現。總結來說,本研究建立了一套利用高解析度熔解變異分析的方法來偵測SLC25A13基因變異。更進一步探討出citrin缺陷可能是經由氧化壓力造成精胺丁二酸合成酵素的表現下降,並且利用甘胺酸可減低此酵素下降的情形。
英文摘要 Citrin, encoded by SLC25A13 gene, is a calcium-dependent mitochondrial solute transporter with a crucial role in urea, nucleotide and protein synthesis pathway. It exchanges mitochondrial aspartate for cytosolic glutamate and transports cytosolic NADH reducing equivalent to mitochondria. Citrin defect causes two phenotypes, type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). Clinical presentations in patients with citrin defect include unbalance of NADH/NAD+ and decrease of liver-specific argininosuccinate synthetase (ASS). Previous studies indicated a high carrier rate of SLC25A13 mutation in East Asia. This study aimed to develop a high-resolution melting analysis for SLC25A13 gene mutation scanning and determine the carrier rate in Taiwan. We also investigate the mechanism of citrin defect-induced ASS decrease and whether glycine treatment would ameliorate the decreased ASS expression. DNAs from normal controls (n=384), HCC patients (n=28) and NICCD patients (n=7) were scanned in exons 6, 9, 11, 16, 17 and parts of introns 6, 10 and 11 of the SLC25A13 gene using the HR-1 instrument. Changes of ASS expression and metabolites concentrations in Huh-7 cells treated with H2O2 or menadione were examined by western blotting and liquid chromatography tandem mass spectrometry, respectively. The ratio of lactate to pyruvate was calculated to assess NADH/NAD+. In addition, Huh-7 cells were transfected with shRNA expression vector targeting to citrin gene by electroporation. Results from gene scanning show that mutation 851del4 is the most common variant found in Taiwan with a carrier rate of 2.3%. Together, the overall mutation carrier rate was 1/30 in healthy subjects, with two novel mutations Q159X and R553Q found. Oxidative stress reduced the ASS expression in a dose-dependent manner in Huh-7 cells. The down expression effect persisted to 12 h with 0.5mM H2O2 treatment. The menadione-induced oxidative stress and the concomitant decline in the ratio of GSH/GSSG were demonstrated in Huh-7 cells in dose-dependent and time-dependent manners. SLC25A13-specific shRNA knocked down the expression of citrin in transfected Huh-7 cells at 48h. The ratio of lactate/pyruvate was increased after citrin knockdown, compared to control group. Pre-treatment of 5 mM glycine for 6 h or 10 mM glycine for 4 hours in Huh-7 cells blunted the reduced ASS expression caused by menadione treatment. In conclusion, a high-resolution melting mutation analysis was established for detecting of SLC25A13 variants. Down-regulation of ASS expression by citrin defect may be through oxidative stress and glycine may blunt the decreased ASS expression.
論文目次 Index
Abstract (in Chinese)…………………………I
Abstract (in English)…………………………………… III
Index………………………………………………………………………………... V
Table list…………………………………………………………………………….. VII
Figure list…………………………………………………………………………… VIII
Appendix list……………………………………………………………………….. IX
Introduction
Urea cycle disorder…………………………………………………………… 1
ASS and citrullinemia………………………………………………………… 1
Citrin and citrin deficiency…………………………………………………… 3
adult-onset type II citriullinemia (CTLN2)…………………………………… 3
Neonatal intrahepatic cholestatic disease (NICCD)…………………………. 4
Frequency and mutations of SLC25A13 gene………………………………... 5
Pathogenesis of fatty liver, NAFLD and HCC………………………………. 6
Treatment of citrin deficiency……………………………………………….. 7
Oxidative stress and citrin deficiency……………………………………….. 9
Glycine………………………………………………………………………. 9
Aims and strategies……………………………………………………………….. 12
Material and Methods
1. Genomic DNA extraction……………………………………………….. 13
2. Mutation scanning of SLC25A13 gene by high-resolution melting analysis 14
3. Genotyping by ABI 7900……………………………………………….. 15
4. Cell culture………………………………………………………………. 15
5. Total protein analysis…………. ……………………………………….. 16
6. Western blotting………………………………………………………… 17
7. SLC25A13 gene knock-down…………………………………………... 20
8. Changes of LDH after treatment of H2O2……………………………… 20
9. Measurement of intracellular GSH and GSSG………………………… 21
10. Metabolites measurement by LC-MS/MS……………………………… 22
11. H2O2-induced oxidative stress and ASS expression……………………. 24
12. Menadione-induced oxidative stress and ASS expresson……………… 25
13. Effects of glycine on ASS expression………………………………….. 25
14. Statistical analysis……………………………………………………… 26
Results…………………………………………………………………………… 27
Discussion……………………………………………………………………….. 32
Conclusion………………………………………………………………………. 36
References………………………………………………………………………. 37
Tables……………………………………………………………………………. 51
Figures…………………………………………………………………………… 54
Appendixes………………………………………………………………………. 67
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