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研究生：	邱于恬 Chiu, Yu-Tien
論文名稱：	台灣男性DAZL基因單一核苷酸多型性之功能分析 Functional Analysis of Single-Nucleotide Polymorphism of the Deleted-in-Azoospermia-Like Gene in Taiwanese Men
指導教授：	郭保麟 Kuo, Pao-Lin
學位類別：	碩士 Master
系所名稱：	醫學院 - 生物化學暨分子生物學研究所 Department of Biochemistry and Molecular Biology
論文出版年：	2007
畢業學年度：	95
語文別：	英文
論文頁數：	85
中文關鍵詞：	類無精症缺失基因、不孕症、造精過程、睾丸特異蛋白質1 、轉譯調控、絲胺酸酥胺酸激酶蛋白質31
外文關鍵詞：	infertility, spermatogenesis, DAZL, TPX1, STK31, translational control
相關次數：	點閱：67 下載：1
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全世界大約有百分之十至十五比例的夫婦受到不孕症的影響，其中男性與女性的因素各占了一半。在不孕男性的Y染色體長臂之AZFc區域上，無精症缺失基因的缺失最為常見，其位於三號體染色體的同源基因類無精症缺失基因也同樣專一表現於生殖細胞，而且這兩者的蛋白質產物都具有高度保留性的RNA-binding motif以及特定的DAZ repeat。類無精症缺失基因在生殖細胞的分化過程中扮演重要的角色，研究指出在基因剔除的小鼠中，造成生殖細胞的缺失；以及影響受質是在轉譯調控的階段。我們在之前的研究中發現，類無精症缺失基因轉錄子在造精過程有所缺陷的男性中，表現量較低。為了闡明類無精症缺失基因在人類造精過程中扮演的角色，我們從二百三十一位患有嚴重寡精蟲症與非輸精管阻塞無精蟲症之台灣不孕男性中篩選變異，找到二個單一核苷酸多型性，分別在核苷酸260 (T12A)與386 (T54A)位置由adenine轉變成guanine，和二個突變點，分別在核苷酸382 (D52E)與427 (K67N)位置由thymine轉變成guanine和adenine轉變成cytosine。其中386位置單一核苷酸多型性在病人較為盛行，為了闡明單一核苷酸多型性和突變點在功能上的意義，我們試圖找出與人類類無精症缺失基因作用的mRNA，經由tether function assay分析，發現SDAD1、絲胺酸酥胺酸激酶蛋白質31、睾丸特異蛋白質1、MVH為類無精症缺失基因的受質。其中T12A和T54A變異點對於降低睾丸特異蛋白質1轉譯效率有關；T12A、D52E、K67N變異點則是對於降低絲胺酸酥胺酸激酶蛋白質31的表現有關；而所有的變異點都與降低MVH蛋白質表現有關，這個結果暗示著不同變異點在造精過程中作用於不同基因時，擁有不同的影響。除此之外，利用RNA-EMSA的實驗，確認睾丸特異蛋白質1和絲胺酸酥胺酸激酶蛋白質31為類無精症缺失基因的受質，更進一步定義出在睾丸特異蛋白質1三端未轉譯區上核苷酸第1-101與第301-414為類無精症缺失基因結合的區域，然而變異點的蛋白質也同樣可以與睾丸特異蛋白質1和絲胺酸酥胺酸激酶蛋白質31結合，這個研究發現變異的蛋白質影響受質並非是經由結合與否，而是可能影響到其它參與在類無精症缺失基因變異點致病機轉的蛋白質。

Infertility affects 10–15% of all couples, and impaired sperm production accounts for about half of these cases. Deleted in Azoospermia (DAZ) gene was originally isolated from the AZFc region on the long arm of the human Y chromosome that is frequently deleted in infertile men. DAZ-like (DAZL), an autosomal homolog located on chromosome 3p24, are expressed exclusively in the germ cells, and their protein products contain a highly conserved RNA-binding motif and a unique DAZ repeat. DAZL gene is essential for the differentiation of germ cells. Loss of germ cells was observed in Dazl knockout mice. And the effect of DAZL regulate substrate is on the translational control. We have previously found that the DAZL transcript amounts were lower in men with spermatogenic failure. To investigate the role of the DAZL gene in human spermatogenesis, DAZL was genotyped in 231 infertile Taiwanese men presenting with severe oligozoospermia and nonobstructive azoospermia. We identified two polymorphisms－A to G transition at nucleotide 386 in exon 3 (T54A), and nucleotide 260 in exon 2 (T12A); as well as two mutations: T to G transversion at nucleotide 382 in exon 3 (D52E) and A to C transversion at nucleotide 427 in exon 3 (K67N). The frequency of T54A allele was found to be more prevalent in patients than in controls (P=0.0004). To characterize the functional significance of DAZL polymorphisms or mutations, we identified the mRNA substrates that are specifically bound by human DAZL protein. We found that SDAD1, STK31, TPX1, MVH were the substrates of DAZL by the tether function assay analysis. Meanwhile, T12A and T54A were associated with decreased translational efficiency for TXP1. T12A, D52E, and K67N of DAZL were associated with decreased protein expression of STK31. All polymorphisms and mutations decreased protein expression of MVH. These results suggest that different polymorphisms may exert different effects on different genes during spermatogenesis. By using RNA-EMSA, we confirmed that TPX1 and STK31 were indeed DAZL substrates. In addition, by using RNA-EMSA, we define 3’UTR 1bp-101bp and 301-414bp of TPX1 interacts with DAZL. However, the variant DAZL proteins also bind to TPX1 and STK31. These findings suggest mutant proteins regulate substrates translation not directly through their binding activity. Other DAZL interacting partners may be involved in pathogenesis of these genetic variants and polymorphisms.

ABSTRACT IN CHINESE..................................i 
ABSTRACT IN ENGLISH..................................iii 
ACKNOWLEDGMENTS......................................v
TABLE OF CONTENTS....................................vi 
LIST OF TABLES.......................................xii 
LIST OF FIGURES......................................xiii 
LIST OF ABBREVIATIONS................................xv 
INTRODUCTION......................................1
1 Pathogenesis of male infertility.................1
2 Process of mammalian spermatogenesis.............1
3 Histology of primary spermatogenesis impairment..3
4 Sterile genes....................................3  
5 Y chromosome and male infertility................4
6 The roles of DAZ and DAZL gene in spermatogenesis4
7 Functions of Dazl................................5
7.1 Several substrates are elucidate by diverse        approach.............................................5
7.1.1 Cdc25C...................................6
7.1.2 Cdc25A...................................6
7.1.3 Tpx1.....................................6
7.1.4 Sdad1....................................7
7.1.5 Mvh......................................8
7.1.6 Stk31....................................8
7.1.7 Sycp3....................................9
7.2 Consensus binding sequence of DAZL...........9
7.3 The phenotype of Dazl mutant animals.........10
7.4 Dazl regulates substrates on the translational level................................................10 
8 Objectives of this study.........................10

MATERIALS AND METHODS..............................12
1 Cell culture.....................................12
1.1 Maintenance and subculture...................12
1.2 Cell stock...................................12
2 Genotyping for infertile men.....................12
2.1 Subjects.....................................12
2.2 Genotyping...................................14 
3 Total RNA isolation..............................15
3.1 Materials....................................15
3.2 Method.......................................15
4 Reverse Transcriptase-Polymerase Chain Reaction, 
RT-PCR...............................................16
4.1 Materials....................................16
4.2 Method.......................................16
5 Real-Time PCR....................................18
5.1 Materials....................................18
5.2 Method.......................................18
6 SDS-polyacrylamide Gel Electrophoresis and Western Blot.................................................19
6.1 Materials....................................19
6.2 Method.......................................21
7 Plasmid DNA preparation and DNA purification.....22
7.1 PCR clean up.................................22
7.2 Gel Extraction...............................23
7.3 Minipreparation of Plasmid DNA...............24
7.4 Midi/Maxipreparation of plasmid DNA..........25
8 Generation of constructs.........................26
8.1 Construction of pcDNA3.1 V5 (B)-MS2-hDAZL His
  tag plasmid........................................27 
8.1.1 Vector...................................27
8.1.2 Primer design............................27
8.2 Construction of GST-hDAZL plasmid............27
8.2.1 Vector...................................27
8.2.2 Primer design............................27
8.3 Construction of reporter plasmid with 3’UTR
  -MS2 hairpin of candidate substrates...............28 
8.3.1 Vector...................................28
8.3.2 Primer design............................28
8.4 Construction of series deletion pGEM-T easy-
  TPX1 3’UTR plasmid................................29
8.4.1 Vector...................................29
8.4.2 Primer design ...........................29
8.5 Construction of truncated pGEM-T easy-STK31 
  3’UTR plasmid.....................................29 
8.5.1 Vector...................................30
8.5.2 Primer design............................30
8.6 Restriction enzyme digestion30
8.7 Ligation.....................................30
8.8 Transformation...............................31
9 Site-directed mutagenesis........................31
9.1 Primer design................................32
10 Tether function assay (Transient transfection and luciferase assay)....................................33
10.1 Transient transfection......................33
10.2 Dual luciferase assay.......................34
11 Statistical analysis............................35 
11.1 Materials...................................35
11.2 Method......................................35
12 Gene expression and protein purification........35
12.1 Gene expression.............................35
12.2 Protein purification........................35
13 RNA-electrophoretic mobility shift assay 
(RNA-EMSA)...........................................36
13.1 In vitro transcription and 32P isotope label 
RNA probe............................................36
13.2 Electrophoresis.............................37
14 Biotin pull-down assay..........................38
14.1 In vitro transcription of biotin probe........38 
14.2 Biotin probe pull-down assay..................39
15 Computational analysis..........................40 
15.1 Restriction enzyme site prediction.........40
15.2 Multiple sequence alignment................40

RESULTS............................................41
1 Genotyping for DAZL in the fertile and infertile men..................................................41
2 Verify DAZL substrates in human..................41
3 TPX1 was specifically bound by DAZL..............42
4 Effect of genetic variants on TPX1...............43
5 STK31 was specifically bound by DAZL.............43
6 Effect of genetic variants on STK31..............44
7 Functional analysis of DAZL SNP for MVH..........44
DISCUSSIONS........................................45
1 The role of DAZL in spermatogenesis..............45
2 The possible role of DAZL variant in spermatogenesis......................................45
2.1 The amino acid conservation of DAZL variants during evolution.....................................46
2.2 The possible protein modification at amino 
acid of variant......................................46
3 How DAZL variants regulate TPX1..................48
4 How DAZL variants regulate STK31.................49
5 Conclusion.......................................49

REFERENCES...........................................51 TABLE................................................63
FIGURE...............................................65
APPENDIX.............................................82
CURRICULUM VITAE.....................................85
                                    

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校內：2009-07-26公開
校外：2009-07-26公開

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