系統識別號 U0026-2409201223414200
論文名稱(中文) 探討突變型SEPT12干擾SEPT6/7/12/12/7/6絲狀物質的形成與在精子環體缺陷的男性不孕症之關係
論文名稱(英文) Interference of SEPT6/7/12/12/7/6 Filament Formation by Mutant SEPT12 Results in Male Infertility with Defective Sperm Annulus
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 101
研究生(中文) 郭勇哲
研究生(英文) Yung-Che Kuo
學號 s58951447
學位類別 博士
語文別 英文
論文頁數 110頁
口試委員 指導教授-郭保麟
中文關鍵字 SEPT12  SEPT7  突變型SEPT12  GTP水解酶  絲狀物形成  septin複合體  septin組裝  生殖細胞  精子環體  不孕症 
英文關鍵字 SEPT12  SEPT7  mutant SEPT12  GTPase  filament formation  septin complex  septin assembly  germ cell  sperm annulus  infertility 
中文摘要 Septin家族為一群具有GTP水解酶活性的蛋白,參與各種細胞內不同的生理活動,包括細胞質的分裂以及細胞型態分化等功能的執行。SEPTIN 12 (SEPT12)為睪丸特異性基因,且在男性精細胞之後期分化扮演了重要的角色。目前我們在不孕症病人的檢體中發現了兩個SEPT12的點突變,分別為c.266C>T/p.Thr89Met以及 c.589G>A/p.Asp197Asn。這兩個點突變均位於GTP鍵結功能區,且藉由電腦軟體模擬也預測點突變會改變蛋白質立體結構。實驗發現Thr89Met點突變(SEPT12T89M)顯著地降低了GTP水解作用,而Asp197Asn點突變(SEPT12D197N)則影響了GTP結合至GTP鍵結功能區的能力。我們也發現此兩組突變型SEPT12均藉由劑量依存方式來影響野生型SEPT12絲狀結構的形成。攜帶有SEPT12D197N點突變之病人為精子稀少且活動力不佳之病徵,而帶有SEPT12T89M之病人則為精子活動力不佳及型態異常之病徵。其中SEPT12D197N之病人之典型特徵為尾部彎曲並伴隨著精子環體結構破損,以及在型態異常之精子上觀察到環體部位缺少SEPT12蛋白的現象。我們確認了SEPT12WT與SEPT7有直接交互作用的關係,但突變型SEPT12無法與SEPT7作有效之結合,且突變型SEPT12與SEPT7並未分布在細胞內同一個位置上,因此我們推測SEPT12WT以及SEPT7是藉由GTP鍵結功能區之界面(G-interface)來作結合。在造精過程中,SEPT7/SEPT12的聚合對於SEPT12相關複合體的組裝扮演關鍵性角色,而SEPT7在全身每個組織都有表現,因此我們也認為在體細胞中,SEPT7對於septin絲狀物形成也很重要。在此,我們發表了存在於生殖細胞中的2組septin複合體: “SEPT6-SEPT7-SEPT12” (SEPT6-7-12) 和 “SEPT2-SEPT6-SEPT7-SEPT12” (SEPT2-6-7-12) 。這些複合體已證實消失在帶有SEPT12D197N點突變之病人精子的環體中。總結以上,SEPT6-7-12 或SEPT2-6-7-12絲狀物模型提供新的佐證來說明精子環體中SEPT12相關絲狀物的組成份。我們的研究也說明功能變異之突變型SEPT12的確會瓦解蛋白絲狀物質的形成,進而破壞精子結構的完整性。
英文摘要 Septins are members of the GTPase superfamily, which has been implicated in diverse cellular functions including cytokinesis and morphogenesis. SEPTIN 12 (SEPT12) is a testis-specific gene critical for the terminal differentiation of male germ cells. We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTP-binding domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation (SEPT12T89M) significantly reduced guanosine-5’-triphosphate (GTP) hydrolytic activity, and the p.Asp197Asn mutation (SEPT12D197N) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild-type SEPT12 in a dose-dependent manner. The patient carrying SEPT12D197N presented with oligoasthenozoospermia, whereas the SEPT12T89M patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12D197N patient included defective annulus with bent tail and loss of SEPT12 from the annulus of abnormal sperm. We also found that SEPT12WT direct interacts with SEPT7. However, mutant SEPT12 proteins neither interacts nor co-localizes with SEPT7, suggesting interaction of SEPT12/SEPT7 is mediated through the GTP-binding domain interface (G-interface). Intriguingly, SEPT12/SEPT7 dimerization is critical for the assembly of SEPT12-related complex during spermatogenesis; moreover, SEPT7 is ubiquitously expressed, suggesting SEPT7 may also essential for other filaments assemblies in somatic cells. Two models are proposed about oligomeric complex of SEPT12 in the male germline. These two models are “SEPT6-SEPT7-SEPT12” (SEPT6-7-12) and “SEPT2-SEPT6-SEPT7-SEPT12” (SEPT2-6-7-12). These models are confirmed by the observation that SEPT2, SEPT6, SEPT7 and SEPT12 are dislocalized at sperm annulus of the SEPT12D197N patient. Taken together, we provide the first evidence that SEPT6-7-12 or SEPT2-6-7-12 complex participates in formation of SEPT12-filament in the mammalian sperm. We also prove mutations in SEPT12 disrupted sperm structural integrity by perturbing septin filament formation.
論文目次 Chinese Abstract (摘 要) I
Abstract II
Acknowledgment IV
Table of Contents VI
List of Tables IX
List of Figures X
Abbreviation List XII

Chapter I. Introduction 1
1.1 Male infertility 1
1.1.1 Spermatogenesis and spermiogenesis 1
1.1.2 The risk factors of male infertility 2
1.1.3 The genetic factors of male infertility 2
1.2 The septin family 4
1.2.1 The structural functions of septin 5
1.2.2 The biological roles of septin 6
1.2.3 The reproductive functions of septin 7
1.2.4 Septin-correlated diseases 8
1.3 SEPTIN 12 (SEPT12) 9
1.3.1 The historical background of SEPT12 10
1.3.2 The biological roles of SEPT12 10
1.3.3 SEPT12 and male infertility 12
1.4 Objectives and specific aims 13

Chapter II. Materials and methods 14
2.1 Clinical Information 14
2.2 Mutation Analysis 15
2.3 Plasmids Construction and Transfection 15
2.4 Recombinant SEPT12 Induction and Purification 17
2.5 GTP Binding and Hydrolysis Assay 18
2.6 GST Pull-down Assay 19
2.7 Immunoprecipitation Assay, Western Blot Analysis and Immunofluorescence Staining 20
2.8 Semi-quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR) 21
2.9 Silver Staining 22
2.10 Atomic Force Microscopy System 22
2.11 Motile Sperm Organelle Morphology Examination (MSOME) and Transmission Electron Microscopy (TEM) 23
2.12 ClustalW Multiple Sequence Alignment 23
2.13 Three-dimensional Structure Analysis and Image Preparation 25
2.14 Statistical Analysis 25

Chapter III. Results 26
3.1 Two novel missense mutations in the SEPT12 gene 26
3.2 Structural alterations of SEPT12T89M and SEPT12D197N 27
3.3 The GTP-binding and hydrolysis functions were perturbed by SEPT12 mutations 28
3.4 Formation of SEPT12 filamentous structure is inhibited by mutant SEPT12 proteins in a dose-dependent manner 29
3.5 SEPT12 was missing from the annulus in the infertile man carrying SEPT12D197N 31
3.6 SPET12 interacts with SEPT1, 4, 6, 7, 11, and 12 33
3.7 Loss of interaction between mutant SEPT12 and SEPT7 33
3.8 SEPT12 interacts with SEPT7 through the GTP-binding domain 34
3.9 Hexameric complex (SEPT6-7-12-12-7-6) as core component of the SEPT12-filament 36
3.10 Octameric complex (SEPT12-7-6-2-2-6-7-12) as core component of the SEPT12-filament 38
3.11 SEPT2, 6, 7, and 12 were missing from the sperm annulus in the infertile man carrying SEPT12D197N 40
Chapter IV. Discussion 41
4.1 GTP binding and hydrolase activity of SEPT12 mutant proteins 41
4.2 Dominant negative effect of the mutant proteins on filament formation 42
4.3 Alteration of protein interaction affinity between mutant SEPT12 and other septins 44
4.4 SEPT12 plays a pivotal roles in the assembly of germline-specific septin filament 45
4.5 The role of SEPT7 in filament formation 47
4.6 Disassembly of hetero-oligomeric SEPT12 filament 50
4.7 Organization of the septin filaments in the mammalian sperm 51
4.8 Phenotype of the patients 53
4.9 SEPT12 mutations in infertile men presenting with distinctive sperm pathology 54

Chapter V. Prospective 55

Chapter VI. Conclusion 56

References 58
Tables 71
Figures 73
Appendix 101
Appendix 1. Development of male germ cell. 101
Appendix 2. Genetic basis of human male infertility defects: spermatogenesis and sperm function. 102
Appendix 3. Genetic basis of human male differentiation defects are multifactorial. 103
Appendix 4. Schematic of prototypical septin structures. 104
Appendix 5. The GTPase switch. 105
Appendix 6. Core architectures of Septin complexes. 106
Appendix 7. Expression pattern and localization of the mouse Sept12 protein. 107
Publications 108
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