中文摘要
論文名稱：
粒線體DNA變異與嬰兒猝死症候群相關性之研究
研究所名稱：台北醫學大學生物醫學技術研究所
研究生姓名：黃純英
畢業時間：九十四學年度第二學期
指導教授：高淑慧助理教授 生物醫學技術研究所

嬰兒猝死症候群（Sudden Infant Death Syndrome, SIDS）至目前為止，確切的原因仍不明，回溯許多文獻報告，SIDS的發生可能與粒線體基因（mitochondrial DNA, mtDNA）突變有關，本篇研究即針對嬰兒猝死症候群（SIDS）、非嬰兒猝死症候群（non-SIDS）及正常對照組（live health control）探討粒線體DNA變異與SIDS之間的相關性。另外也探討DNA修補機制有關的酵素hOGG1基因多型性與SIDS之間的相關性。本研究中我們收集7位SIDS及19位non-SIDS的個案。死亡個案採取血液、骨骼肌及心肌組織，正常對照組則採取正常嬰兒的唾液檢體（buccal epithelial sample），利用聚合酶鏈鎖反應（polymerase chain reaction, PCR）、Long-extension PCR、Primer-shift PCR及即時定量PCR（Real-time Quantitative PCR ）技術，分析mtDNA hypervariable region I（HVR I）、HVR II變異情形、mtDNA斷損突變（large-scale deletion）及相對mtDNA拷貝數（relative amount of mtDNA copy number）。實驗結果發現，SIDS、non-SIDS及live health control三組之mtDNA HVR I、HVR II DNA序列變異情形，包括鹼基的取代（DNA substitution）種類、位置及數目並無顯著差異。於本研究中檢測有三種mtDNA deletion於SIDS及non-SIDS檢體中，分別為4977 bp、5335 bp及7599 bp deletion。live health control的buccal epithelial sample中僅發現一位有7599 bp deletion。4977 bp deletion僅出現在一位non-SIDS死於先天性心臟畸形的心肌樣品中。比較SIDS於不同組織的mtDNA deletion發生率，發現骨骼肌的5335 bp deletion發生率高出心肌及血液有1.5及2倍，另骨骼肌的7599 bp deletion發生率高出血液及心肌有1.6倍。比較SIDS與non-SIDS之間5335 bp及7599 bp deletion發生率的差異，發現SIDS血液5335 bp deletion高出non-SIDS血液4倍，SIDS骨骼肌5335 bp deletion高出non-SIDS骨骼肌1.8倍。SIDS血液中7599 bp deletion高出non-SIDS血液有2倍。SIDS victims於血液及骨骼肌的multiple deletion發生率高出non-SIDS血液及骨骼肌有4倍及2倍。利用費雪精準檢定(Fishers’ Exact Test)比較SIDS與non-SIDS之間於血液、骨骼肌及心肌的mtDNA deletion，發現並沒有顯著性差異(p>0.05)，其中骨骼肌5335 bp deletion 之p值為0.093，趨近於0.05。統計SIDS與non-SIDS於血液、骨骼肌及心肌multiple deletion的比率，兩組之間亦沒有顯著性差異，其中骨骼肌之p值為0.085，趨近於0.05。SIDS victims骨骼肌與心肌的相對mtDNA copy number均高於non-SIDS victims約0.4倍，但SIDS victims其血液的相對mtDNA copy number反而比non-SIDS victims低。比較SIDS 與non-SIDS victims在血液、心肌及骨骼肌中相對mtDNA copy number，並無顯著性差異，p值分別為0.25、0.28及0.14。SIDS的骨骼肌及心肌比non-SIDS有較高的deletion發生率及較高的相對mtDNA數目，此現象可能係因帶有mtDNA缺損的粒線體因生物能量不足，所產生的補償機制，使粒線體增殖，mtDNA copy number相對的升高。而SIDS group血液的mtDNA deletion發生率高於non-SIDS，但相對mtDNA數目卻比non-SIDS group低，此種不同於骨骼肌及心肌代償作用的結果，是否與mtDNA deletion引發apoptosis作用於骨髓幹細胞有關，仍有待進一步研究。另外，分析SIDS、non-SIDS及live health control的hOGG1基因型，SIDS victims的1245G allelic frequency為0.786，較non-SIDS的0.611及正常對照組的0.450高，比較SIDS與live health control 及non-SIDS與live health control三種hOGG1基因型，發現並沒有顯著性差異，p值分別為0.062及0.246。雖然SIDS及non-SIDS與live health control之唾液檢體來源不同，但整體而言SIDS及non-SIDS之斷損突變發生率比live health control高出許多倍。mtDNA斷損除了使細胞內的生物能量產生危機外，也可能會促進細胞apoptosis。過去的研究指出許多SIDS在腦幹的病理檢查發現有apoptosis，而這些apoptosis被認為與缺氧有關。綜合實驗結果，我們的結論認為mtDNA deletion本身並非直接與SIDS的死因有關係，但或許可能當嬰兒處於發育階段的脆弱時期，由於mtDNA deletion，嬰兒易受到能量不足或缺氧的間接的作用下，導致嬰兒有猝死發生的傾向。

Abstract
The Sudden Infant Death Syndrome (SIDS) is one kind of leading cause of postneonatal infant death which also rises a difficult problem between the legal and medical systems. SIDS is defined as the sudden death of an infant less than 12 month old that remains unexplained after a complete clinical review, autopsy and death scene investigation. Despite the fact that many hypotheses have been proposed, the causes of SIDS are still uncertain. Although a number of coding region mtDNA mutations involving SIDS have been reported, the role of mtDNA variations in SIDS victims is still not known. The purpose of this study was to investigate whether the mtDNA variations or large-scale deletion exert any effect on the etiology of SIDS. Moreover, the biologic significance of the hOGG1 1245C"G polymorphism for SIDS has not yet been elucidated. The polymorphism of the hOGG1 gene was assessed by using a PCR-restriction fragement length polymorphism (RFLP) method. Seven SIDS and nineteen non-SIDS victims were enrolled. We determined the relative amount of mtDNA copy number and the occurrence of mtDNA deletion in blood, skeletal muscle and cardiac muscle from both SIDS and non-SIDS group using real-time quantitative PCR, primer-shift PCR analysis and DNA sequencing. Buccal epithelial samples from twenty age-matched live health control subjects were also examined. In this study we also explore the DNA sequence variation of D-loop hypervariable region I(HVR I) and HVR II. D-loop sequence of all subjects were sequenced and compared with the Cambridage sequence. The mean number of substitutions in HVR I and HVR II between SIDS, non-SIDS and live health control were no significant difference. Three types of mtDNA deletions were found in this study such as 4977, 5335 and 7599 bp deletion. The breakpoints of deletion were identified by sequencing method. In live health control group only one subject was found with 7599 bp deletion from buccal epithelial sample. Only one specimen was found with 4977 bp mtDNA deletion from cardiac muscle in congenital heart malformation subject. The frequencies of occurrence of 5335 and 7599 bp deletions in SIDS and non-SIDS were much higher than live health control group. There were no statistically significant difference associated with the frequencies of occurrence of 5335 bp and 7599 bp mtDNA deletions between SIDS and non-SIDS victims was found. The frequency of occurrence of 5335 and 7599 bp mtDNA deletion in blood from SIDS were four and two fold to non-SIDS, respectively. The frequency of occurrence of 5335 bp mtDNA deletion in skeletal muscle was 1.8 fold to non-SIDS. No significant correlation between the relative amount of mtDNA copy number and the frequencies of occurrence of mtDNA deletions in SIDS and non-SIDS. The allelic frequency of hOGG1 1245G was 78.6 % in SIDS, 61.1 % in non-SIDS and 45.0 % in live health control. The genotypic frequencies were no statistically significance between SIDS and live health control(p=0.062) and between non-SIDS and live health control(p=0.246). These defects in mtDNA may result in impaired production of ATP or sensitized cells to apoptosis. We proposed that mtDNA deletions in themselves do not cause SIDS but may cause energy deficiency or hypoxia in stressful situation during a vulnerable developmental stage. So the primitive results of mitochondrial DNA deletion might predispose infant to death in critical situations.

目錄
中文摘要……………………………………………………………………I
英文摘要……………………………………………………………………V
目 錄…………………………………………………………………..VIII
圖表目錄……………………………………………………………………..X
縮 寫 表…………………………………………………………………...XII

第一章 緒論………………………………………………………………..1
一、 嬰兒猝死症候群的定義…………………………………………..1
二、 嬰兒猝死症候群病因假說………………………………………..2
三、 人類粒線體及粒線體DNA……………………………………….5
四、 粒線體DNA高變異區序列多型性(Hypervariable Region, HVR)與SIDS之相關性………………………………………………….8
五、 粒線體DNA的突變及斷損……………………………………….9
六、 DNA修補機制……………………………………………………11

第二章 實驗材料與方法………………………………………………….13
一、 研究對象………………………………………………………….13
二、 DNA萃取…………………………………………………………13
三、 DNA定量…………………………………………………………15
四、 合成核酸引子(Oligonucleotide primer)…………………...……..15
五、 HV I及HV II定序分析(Sequencing)……………………………16
六、 Long extension PCR……………………………………………...18
七、 Primer-shift PCR………………………………………………….18
八、 瓊膠電泳(Electrophoresis)……………...………………………..19
九、 瓊膠DNA擷取(Gel extraction)及定序分析(sequencing)……….20
十、 及時定量PCR(Real-time quantitative PCR)………………….….20
十一、 hOGG1基因型分析…………………………………………...21
十二、 統計分析………………………………………………………23

第三章 實驗結果………………………………………………………….24
一、 HV I區域變異分析………………………………………………24
二、 HV II區域變異分析……………………………………………...24
三、 長片段mtDNA斷損……………………………………………..25
四、 Primer-shift PCR確認斷損突變…………………………………26
五、 斷損mtDNA的序列分析………………………………………..27
六、 SIDS、non-SIDS及live health control斷損突變發生率………27
七、 拷貝數分析(mtDNA copy number)……………………………...29
八、 hOGG1基因型分析………………………………………………30

第四章討論………………………………………………………………….31

附表及圖…………………………………………………………………….39
參考文獻…………………………………………………………………….67


圖表目錄

Table 1 Genes encoded by human mitochondrial DNA……………………………39

Table 2 Characteristics of SIDS, non-SIDS and live health control group………...40

Table 3 General profiles of each cases……………………………………………..41

Table 4 The DNA sequences of oligonucleotide primers used for the analysis
of the 4977 bp, 5335 bp and 7599 bp mtDNA deletion…...……………....42

Table 5 Oligonucleotide primers used for the determination of the 4977 bp
, 5335 bp and 7599 bp mtDNA deletion………………………………..….43

Table 6 The DNA sequences of oligonucleotide primers used for real-time quantitative PCR…...……………………………………………………...44

Table 7 The DNA sequences of oligonucleotide primers used for the analysis
Of mtDNA HV I region, HV II region and hOGG1 gene………….…..….45

Table 8 MtDNA substitution of HVR I in SIDS, non-SIDS and live health
control groups……………………………………………………………...46

Table 9 MtDNA substitution of HVR II in SIDS, non-SIDS and live health
control groups……………………………………………...........................47

Table 10 Frequencies of occurrence of mtDNA deletions in SIDS, non-SIDS
and live health control specimens…………………………………………48

Table 11 Heteroplasmy of mtDNA deletions in SIDS group……………………….49

Table 12 Relative amount of mtDNA copy number in SIDS, non-SIDS and
live health control specimens…………………………………………..….50

Table 13 Genotypes and allelic frequencies of the hOGG1(1245CgG)
polymorphism among SIDS, non-SIDS and live health control…………..51

Fig. 1 General structure and intraorganellar organization of mitochondrion…….52

Fig. 2 Schematic representation of the mitochondrial respiratory chain…………53

Fig. 3 Human mtDNA genome…………………………………………………...54

Fig. 4 Cycle number and melting curvein real-timePCR…………...…………....55

Fig. 5 Genomic structure of hOGG1 and RFLP analysis of the hOGG1
polymorphism…………………………….…………….………………….56

Fig. 6 Long- extension PCR, L8150-H13845 and L8150-H14020……………....57

Fig. 7 Long- extension PCR, L8251-H13845 and L8251-H14020…….…..……58

Fig. 8 5335 bp mtDNA deletion primer-shift PC………………………………...59

Fig. 9 DNA sequence at np 13130-13136 on the light-strand….………………...60

Fig. 10 7599 bp mtDNA deletion primer-shift PCR……….………….…………...61

Fig. 11 DNA sequence of 5335 bp mtDNA deletion………………………………62

Fig. 12 DNA sequence of 7599 bp mtDNA deletion………………………………63

Fig. 13 Frequencies of occurrence of mtDNA deletion mutations…..…………….64

Fig. 14 Relative amount of mtDNA copy number………………….……………...65

Fig. 15 RFLP analysis of the codon 326 hOGG1 Cys/Ser polymorphism
from SIDS victims………………………………….……………………...66

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