臺灣博碩士論文加值系統

青光眼為眼科第二大眼病，第一大不易治療的眼科疾病。因此在WHO.2020.世界視力照護宣導中指出，青光眼是需大力防治的疾病之一。在過去幾年造成青光眼的相關基因逐漸被發現，到目前為止至少發現有14個以上相關的基因造成隅角開放性青光眼，因此青光眼可以被認為不是一個單一基因的疾病。而在不同種族也有不同的發現，在台灣地區醫療已達一定水準之區域，仍少有相關基因之探討。本篇論文乃以先驅者之方式將年輕型且具有遺傳特性(非外傷，手術或其他原因引起)的特殊分類 -- 年輕型隅角開放性青光眼病人，以最具代表性的隅角開放型青光眼(POAG)基因，MYOCILIN (MYOC)和OPTINEURIN (OPTN)做為本研究的分析基因。我們利用聚合酵素連鎖反應(PCR)、基因定序和統計學的方法找尋在這兩個基因可能成為致病之變異。在48位年輕型隅角開放性青光眼和100位正常人的MYOC基因中，我們發現8個多型性(polymorphisms)。另外我們也發現在6位年輕型隅角開放性青光眼患者中帶有4個在MYOC基因的突變點--- c.136C>T (Arg46Stop)、c.158T>C(Val53Ala)、c.604+228A>T 和c.1515+73G>C---所佔的比例為12.5% (6/48)。在OPTN基因篩檢分析中我們並沒有找到任何突變點。然而我們發現了15個多型性(polymorphisms)，包括7個先前被報告過和8個是在本研究中新發現的。其中c.-233+25C>G的變異在病人和正常人間所佔有的比例經統計分析是有明顯區別，且在正常人所佔的比例較高，因此我們認為這個變異點可能具有防止青光眼形成的保護功能。另外要進一步分析青光眼基因時就需要建立青光眼的動物模型，我們的結果顯示大鼠的眼壓正常為21-24 毫米汞柱，在給予類固醇藥物第2周後即可開始看到眼壓開始升高，眼壓上升到28-31毫米汞柱， 持續給藥最高可達32±2.5毫米汞柱。進一步觀察基因表現，我們發現MYOC和OPTN基因的表現都有受到眼壓升高影響而降低。綜合以上研究結果，我們已建立台灣地區年輕型隅角開放性青光眼患者的MYOC和OPTN基因多型性和突變的資料庫，除了在人類年輕型隅角開放性青光眼患者之基因探討外，本研究報告中，我們也建立以類固醇點用於大鼠眼部誘發高眼壓的動物模型，此動物模型將可適用在後續小樑組織分析和青光眼致病基因的研究中使用。這些完整的資料、分子診斷技術和動物模型的發展，可以讓我們對於年輕型隅角開放性青光眼的成因有更深入的瞭解。

Glaucoma is the second cause of blindness all over the world. There will be 200 million people suffered from blindness in 2020. Glaucoma is a complex disease with both genetic and environmental factorial contributing. The genetic components are illustrated by the factor that if relative have the disease, you have a greater risk of getting affected yourself. Early detection and diagnosis is vital to stop the progression of the disease. To be able to do that, it is essential to gain more knowledge about the molecular genetic aspects of the disease. However, in Taiwan, the data of the related genes are still insufficient; therefore, further research is worthy to conduct. The overall goal of this thesis is to establish the genetic basis for the screening, diagnosis, and pathogenesis studies of MYOC and OPTN genes of juvenile-onset glaucoma (JOAG) in Taiwan. We also conduct the pilot study of animal model of ocular hypertension suitable for glaucoma genes mechanism evaluation. In this study, we aim to determine the mutation sites of the MYOC and OPTN genes by using comparative genetic analysis between genomic DNA from normal individuals and JOAG patients; and to understand etiology of MYOC and OPTN genes mutants in JOAG. The analysis revealed four MYOC mutations and six polymorphisms. The prevalence of MYOC gene mutations in this study was 12.5% (6/48). Our results indicate that the c.136C>T (Arg46Stop), c.158T>C (Val53Ala), c.604+228A>T, and c.1515+73G>C mutations of MYOC may be associated with JOAG. Analysis of OPTN gene, fifteen variants of OPTN were found in the study. Seven of the variants have been reported and eight were novel. All of the sequence changes were found in patients with JOAG and in the normal controls except for variant c.-233+25C>G, which was found only in the control group. We suggested the variant c.-233+25C>G may be protective against glaucoma in Taiwanese. In addition, our data indicate that none of the mutations in OPTN are associated with JOAG. In animal model study, our results found the average IOP in normal eyes were 21-24 mmHg. Steroid-treated eyes showed significantly higher IOP than control eyes from 2 to 10 weeks. The average IOP in treated eyes were elevated to 28-31 mmHg after 2 weeks. The higher IOP can be 32±2.5 mmHg. In addition, we found both MYOC and OPTN gene expression significantly decrease than control eyes at the end of the 10-week using RT-PCR analysis. Especially, MYOC gene express significantly decrease more than OPTN gene. In summary, our study provides information for understanding the importance of genetic factors in JOAG of Taiwanese and that may be of use in the improvement of genetic diagnosis and genetic counseling for the families of JOAG in Taiwan. In addition, the animal trial with topical medication produces persistent IOP elevation in rat eyes and may be a promising experimental model for the investigation of the biological mechanisms of glaucomatous optic neuropathy.

致謝(Acknowledgements) i
縮寫表(Abbreviation) iii
中文摘要 1
英文摘要 3
前言(Introduction) 5
青光眼簡介 5
年輕型青光眼簡介 7
MYOCILIN (MYOC)基因簡介 10
OPTINCIN (OPTN) 基因簡介 11
WDR36 基因簡介 11
青光眼動物模型簡介 12
材料與方法 (Material and Methods) 16
結果(Results) 25
MYOC基因突變之篩檢 25
OPTN基因突變之篩檢 27
青光眼動物模型的建立 29
討論(Discussion) 31
未來研究方向(Future works) 38
圖(Figures) 40
表(Tables) 50
參考文獻(References) 62
附錄(Appendix) 77
I附圖 77
II實驗步驟 78
III實驗藥物 82
IV實驗儀器 84

附件：發表文章
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二. Yung-Chang Yen,Jiann-Jou Yang, Ming-Chih Chou , Shuan-Yow Li : Absence of optineurin (OPTN) gene mutations in Taiwanese patients with juvenile-onset open-angle glaucoma ; Molecular Vision 2008; 14:487-494

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