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研究生:林盈宏
研究生(外文):Ying-Hung Lin
論文名稱:Y染色體基因缺失及表現在造精功能
論文名稱(外文):Deletion status and expression profiles of Y chromosomal genes in patients presenting with spermatogenesis defects
指導教授:郭保麟郭保麟引用關係蔡少正
指導教授(外文):Pao-Lin KuoShaw Jeng Tasi
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:112
中文關鍵詞:Y 染色體缺失不孕症
外文關鍵詞:y chromosomedeletioninfertility
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  • 被引用被引用:1
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已婚夫婦中約有15﹪的夫妻有不孕症的困擾, 其中約有一半是男性因素所造成。 於男性不孕症患者中有22.7﹪其致病原因仍不清楚, 但證據顯示遺傳因素扮演重要角色。 近10年來發現有15個基因位Y染色體第5及第六區間上並表現於睪丸組織中。 這15個基因是DFFRY, DBY, UTY, TB4Y, E1F1AY, RBMY1A1, DAZ, BPY1, BPY2, CDY1, CDY2, XKRY, PRY, SMCY, 及 TTY2。 本研究分成兩個部分, 在第一部分我們採用多重引子聚合酶連鎖反應, 以基因特定引子進行這15個基因缺失的篩檢。 我們發現在180位無精蟲或寡精蟲症患者之中, 有19位(10.6%)有一個或一個以上的基因缺失, 而每位基因缺失患者至少有DFFRY, DBY, RBMY1A1及 DAZ四個基因之中, 其中一個基因缺失。 我們推測這四個基因於精子發育過程扮演相當重要的角色。 在第二部份我們採用QC-RT-PCR定量DFFRY, DBY, RBMY1A1及DAZ基因與DAZ的同源基因DAZL及BOULE mRNA在睪丸組織的表現量。 發現於Sertoli cell -only syndrome 病患的睪丸組織中 RBMY1A1、 DAZ、 DAZL及BOULE的mRNA表現量較正常人及hypospermatogenesis + maturation arrest低, 但於正常人及hypospermatogenesis + maturation arrest之間沒有顯著差異。 DFFRY及DBY基因表現量在各組之間則沒有顯著差異。 基因缺失篩檢可以幫助我們了解DFFRY、 DBY、RBMY1A1及 DAZ基因在造精功能上的重要程度。 定量DFFRY、 DBY、RBMY1A1、 DAZ、 DAZL及BOULE基因, 使我們了解這些基因在不同睪丸組織表現型患者之間的差異, 並且利用RBMY1A1、 DAZ、 DAZL及BOULE基因表現量於不同睪丸組織表現型患者之間的差異, 來提供新的分類及診斷睪丸表現型方式。
Abstract:
It is estimated that 15- 20% of couples are infertile and male factors account for about half of the cases. The causes of male infertility are unknown in about 22.7﹪of all cases. There are ample scientific evidences showing that genetic factors are involved in most cases of male-factor infertility. Recently, 15 genes located in interval 5 and 6 of human Y chromosome have been shown to be expressed in the testis. These genes (DFFRY, DBY, UTY, TB4Y, E1F1AY, RBMY1A1, DAZ, BPY1, BPY2, CDY1, CDY2, XKRY, PRY, SMCY, and TTY2) potential AZoospermia Factors (AZFs). We designed a novel multiplex PCR protocol to detect deletion status of the 15 Y-chromosomal genes in Taiwanese patients presenting with azoospermia or severe oligospermia. Of 180 patients screened, 19 (10.6%) had deletion of at least one of four genes: DFFRY, DBY, RBMY1A1 and DAZ. Other genes, SMCY, EIF1AY, PRY, TTY2,CDY1, BPY2, CDY2, and XKRY were also deleted in some cases. It was concluded that DFFRY, DBY, RBMY1A1 and DAZ genes play important roles in human spermatogenesis. To explore the roles of these four genes, we measured the amounts of transcripts of these genes and two DAZ-homologous genes (DAZL and BOULE) by quantitative competitive (QC)—RT—PCR in the testicular tissues of patients. The concentrations of RBMY1A1, DAZ, DAZL and BOULE transcripts were significant lower in man with Sertoli cell-only syndrome (SCO). No significant difference was found for the DBY and DFFRY transcripts between different groups of patients and control subjects. Decreased concentrations of RBMY1A1, DAZ, DAZL and BOULE transcripts in patients with SCO can be ascribed to the secondary effect caused by loss of germ cells in these patients because these four genes are germ-cell specific. In contrast, DBY and DFFRY genes are ubiquitous and the concentrations of their transcripts are no different between patients and controls. Expression profiles of genes expressed in the testicular tissue can help to elucidate the roles of these genes in spermatogenic defects and to provide information regarding categorization of patients.
目錄
中文摘要…………………………………………………………………i
英文摘要………………………………………………………………iii
致謝………………………………………………..….…………………v
目錄……………………………………………………………………vi
圖錄………………………………………………………….……….….x表錄…………………………………………………………………….xiii
壹、序論…………………………………………………………………1
第一節、男性不孕症原因…….…………………………………….1
第二節、男性精子發育過程…………………………………….….4
第三節、精子發育相關基因………………………….…………….5
第四節、Y染色體結構與功能…………………….………………..8
第五節、Y染色體與男性不孕症的關係…………………………..10
第六節、與精子發育異常相關的Y染色體基因…………………12
第七節、DAZ 及其同源基因對精子發育的影響…………16
第八節、研究動機及實驗設計…………………………………….18
貳、材料與方法……………………………………………………….19
第一節、病人的來源及評估方式………………….………………19
第二節、Y染色體基因缺失的診斷………………………………..19
2.1、DNA萃取…………………………………………………..19
2.1.1實驗材料…………………………………………………19
2.1.2實驗步驟…………………………………………………19
2.2、多重引子聚合酶連鎖反應…………………………………21
2.2.1實驗原理…………………………………………………21
2.2.2實驗材料…………………………………………………22
2.2.3實驗步驟………………………………………………..22
2.3、單一引子聚合酶連鎖反應………………………………..23
2.3.1實驗材料……..…………………………………………23
2.3.2實驗步驟………………………………………………..23
2.4、洋菜膠體電泳分析(Agarose gel electrophoresis)…………25
2.4.1實驗材料…...……………………………………………25
2.4.2實驗步驟………………………………………………...25
2.5、聚丙烯醯胺凝膠電泳法(Polyacrylamide gel electrophoresis)26
2.5.1實驗材料………………………………………………..26
2.5.2實驗步驟………………………………………………..26
第三節、候選基因基因在睪丸組織的表現量……………………27
3.1、競爭性定量反轉錄聚合酶連鎖反應(Quantitative copmetitive
reverse transcription polymerase chain reaction)……27
3.1.1 正常控制者(Native control)及競爭者(competitor)的設計原
理……..……………………………………………………………27
3.1.2實驗材料………………………………………………….….28
3.1.3正常控制者(Native control)及競爭者(competitor)….….29
(1)聚合酶連鎖反應(PCR)…………………………………29
(2)選殖(Cloning)……………………………………………30
(3)體外轉錄 (In vitro transcription)…………………....33
(4)標準曲線(Standard curve)的製作…………………....35
3.2、RNA抽取…………………………….………………..……...37
3.2.1實驗材料…………………………………..………..………..37
3.2.2實驗步驟………………………………………..…..………..37
3.3、反轉錄酶反應……………………………………….………..39
3.3.1實驗材料……………………………………..……………....39
3.3.2實驗步驟……………………………………..…….………...39
3.4、聚合酶連鎖反應(PCR)..……………………………………..39
3.4.1實驗材料…………………………………….……………....39
3.4.2實驗步驟…………………………………….………………39
3.5、聚丙烯醯胺凝膠電泳法(Polyacrylamide gel electrophoresis)40
3.6、定量分析…………………………………………….……..40
3.7、統計分析……….…………………………………………..41參、結果………………………………………………………………41
第一節、 Y染色體上基因缺失的診斷………………………….41
第二節、 造成精子發育異常的Y染色體候選基因mRNA表現……………………………………………………….44
第三節、DAZ 及其DAZ同源基因mRNA表現…………..…….46
肆、討論…………………………………………………….………….49
第一節、 Y染色體基因缺失的診斷……………………………49
第二節、 Y染色體基因缺失與睪丸組織的相關分析…………50
第三節、Y染色體缺失交界(deletion junction)………….52
第四節、Y染色體AZFa區域候選基因的mRNA表現量………53
第五節、Y染色體AZFb區域候選基因mRNA表現量…………55
第六節、DAZ及其同源基因mRNA表現量………………………56
第七節、候選基因mRNA表現量的應用………………………..57
參考文獻…………………………………………..………………...59
圖表…………………………………………………………………..66
附錄: 溶液與藥品配製……………………………………..………..109
圖錄
圖一、完整的精蟲發育過程……………………………………………66
圖二、BOULE、DAZL及DAZ基因於生殖細胞的表現……………67
圖三、多重引子混合液1、2、3、4的聚合酶連鎖反應…………….68
圖四、 多重引子混合液1的聚合酶連鎖反應………………………..69
圖五、 多重引子混合液2的聚合酶連鎖反應……………………….69
圖六、 多重引子混合液3的聚合酶連鎖反應……………………….70
圖七、 多重引子混合液4的聚合酶連鎖反應……………………….70
圖八、三個Y染色體AZFa區域基因缺失患者…………………..…..71
圖九、四個AZFb或AZFb + c區域基因缺失患者…………………..72
圖十、十二個AZFc區域基因缺失患者……………………………….73
圖十一、GAPDH基因QC-RT-PCR的標準曲線…………………..74
圖十二、不同型態睪丸組織中GAPDH基因mRNA表現差異……75
圖十三、DFFRY基因QC-RT-PCR的標準曲線……………………76
圖十四、不同組織DFFRY mRNA表現情形………………………..77
圖十五、不同型態睪丸組織中DFFRY基因mRNA表現差異…….78
圖十六、DBY基因QC-RT-PCR的標準曲線………………………..79
圖十七、不同組織DBY mRNA表現情形……………………………80
圖十八、不同型態睪丸組織中DBY基因mRNA表現差異………..81
圖十九、RBMY1A1基因QC-RT-PCR的標準曲線…………………82
圖二十、不同組織RBMY1A1 mRNA表現情形…………………….83
圖二十一、不同型態睪丸組織中RBMY1A1基因mRNA表現差異…84
圖二十二、BOULE基因QC-RT-PCR的標準曲線…………………85
圖二十三、不同組織BOULE mRNA表現情形….………………….86
圖二十四、不同型態睪丸組織中BOULE基因mRNA表現差異….87
圖二十五、DAZL基因QC-RT-PCR的標準曲線………………….88
圖二十六、不同組織DAZL mRNA表現情形……………………….89
圖二十七、不同型態睪丸組織中DAZL基因mRNA表現差異……90
圖二十八、DAZ基因QC-RT-PCR的標準曲線………………….91
圖二十九、不同組織DAZ mRNA表現情形……………………….92
圖三十、不同型態睪丸組織中DAZ基因mRNA表現差異………93
圖三十一、不同型態睪丸組織表現量有統計意義的基因表現情形…94
圖三十二、不同型態睪丸組織中GAPDH基因mRNA表現分佈…95
圖三十三、不同型態睪丸組織中DFFRY基因mRNA表現分佈….96
圖三十四、不同型態睪丸組織中DBY基因mRNA表現分佈……..97
圖三十五、不同型態睪丸組織中RBMY1A1基因mRNA表現分佈…98
圖三十六、不同型態睪丸組織中BOULE基因mRNA表現分佈…99
圖三十七、不同型態睪丸組織中DAZL基因mRNA表現分佈…..100
圖三十八、不同型態睪丸組織中DAZ基因mRNA表現分佈….101
表錄
表一、人類單基因異常引起的不孕疾病………………………………..3
表二、 基因剔除老鼠精子發育異常情形………………………………7
表三、Y染色體上基因之分類…………………………………………11
表四、NRY上12個基因家族成員的分類……………………………102
表五:多重引子混合序列及PCR產物長度………………………….102
表六、單一引子長度及序列…………………………………………102
表七:引子Mix 1配製方法…………………………………………..103
表八:引子Mix 2配製方法…………………………………………103
表九:引子Mix 3配製方法……………………………………….…103
表十:引子Mix 4配製方法………………………………………….103
表十一、候選基因QC-RT-PCR所使用引子之序列……………….104
表十二、19個Y染色體基因缺失的造精功能障礙病人…………...105
表十三、測試缺失交界所用引子……………………………………..105表十四、 12個AZFc缺失病人缺失交界……….…………….……106
表十五、文獻中AZFa區域基因缺失及其睪丸組織表現型………..107表十六、DAZ、DAZL及BOULE基因組織表現形態及基因缺損後的
表現型………….…………………………………….……..108
表十七、五位Y染色體基因缺失患者的候選基因表現量…………108
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