臺灣博碩士論文加值系統

中文摘要

貓多囊腎病是貓最常見的遺傳性疾病，有極高的致死率，侵犯了全世界約36-49 %的波斯貓及波斯相關品種貓隻。多囊腎病的定義為出現在腎臟皮質及髓質各種不同大小充滿液體的囊腫，甚至是肝臟、胰臟及子宮都可以見到。貓PKD1 gene exon 29上的點突變，是造成貓多囊腎病的原因，這個點突變使得PKD1基因產生終止密碼子而無法製造出足夠的正常蛋白質，使得腎臟腎小管細胞異常的增生及凋亡而出現許多不正常的囊腫，並且這個嚴重的疾病有著自體顯性的遺傳模式。許多基因檢測方法被發展用來檢測這個重要的疾病。超音波是目前被廣泛用於診斷多囊腎病的工具，可以見到患貓腎臟中無或低回音性、圓形或卵圓形、與周圍腎臟組織界限分明的囊腫影像。然而,目前大部分與這個疾病相關的文獻不論是影像學或是基因檢測方面，都著重在波斯與波斯相關品種的貓，之前我們實驗室調查的結果發現不但這個疾病在波斯貓有高盛行率，而且短毛品種的貓也有相當大的風險得到這個疾病。在本研究中，我們隨機收集了2008年9月至2010年4月到中興大學獸醫教學醫院就診的短毛品種貓隻，同時進行超音波學檢查並採血後萃取核&;#33527;酸，針對其PKD1基因exon 29進行點突變偵測，並且定序之後與正常序列比對，同時我們也試著從毛囊中抽取DNA，與血液來源的DNA進行交叉比對。在這個研究當中，我們一共收集了179隻以短毛貓為主的樣本進行分析，另外也將所收集到的樣本與本實驗室學姊之前所收集到的111隻以波斯貓為主的樣本合併進行統計分析。這290隻貓主要包含了短毛家貓(43.4%)、波斯貓(32.4%)、金吉拉(10%)、美國短毛貓(5.9%)和其他品種的貓(8.3%)。所有收集到的樣本都進行基因檢測，同時其中的132隻貓針對多囊腎病進行超音波檢測。結果顯示，以超音波及基因檢測多囊腎病在短毛貓的盛行率分別為12%和4%。以超音波檢查診斷為多囊腎病的貓隻在種別、診斷年齡、性別及腎臟指數都與未受侵犯的貓隻沒有顯著相關性，而以基因檢測帶有點突變的卻與性別、品種及被毛長短有顯著相關性，結果顯示雄性、波斯相關品種的貓和長毛貓有較高的風險罹患多囊腎病。與之前本實驗室所調查的結果不同的，短毛家貓患有多囊腎病的機率和其他短毛品種一樣，並沒有特別高，這顯示了之前的調查結果可能有採樣的偏差。其中三隻經過超音波檢查診斷為多囊腎病的貓，其PKD1基因檢測的結果卻正常，這個結果顯示就如同人類一樣，可能有其他基因(點)突變會造成多囊腎病。並且，所有利用PKD1基因檢測出帶有點突變的貓中，只有一隻作了詳細的超音波檢查卻沒有觀察到腎臟囊腫。推究其原因可能該貓只有三歲，囊腫的發展較慢，以致於小到超音波無法觀察到，或許我們可以利用人類的「Two-hit假說」來解釋這個有趣的現象，可能是由於基因、飲食或環境的因素使得該貓的囊腫發展較慢甚至不產生囊腫。由於採集毛髮進行DNA萃取來診斷PKD具有快速、方便、任何年齡均可施行等優點，加上PKD在波斯相關品種貓隻的高盛行率是不容忽視的，故採集毛髮進行基因檢測並同時施行超音波檢查，才能確實掌控疾病的發展並給予適當的治療，並能有效降低未來貓多囊腎病的盛行率。

Abstract

Feline autosomal dominant polycystic kidney disease (PKD), an inherited disorder characterized by the development of renal cysts, is the most prevalent and potentially lethal monogenic disorder in cats. It affected 37-49% Persian and Persian-related cats worldwide. Recently, a CaA transversion resulting in a stop mutation has been identified in PKD affected cats and several gene tests had been established to indentify this point mutation. However, to date prevalent studies both in medical imaging and gene screening of this lethal disease are mainly focus on long-hair breed cats. Previous study of our laboratory revealed that not only Persian but also other domestic short-hair (DSH) breeds had a risk of developing PKD. In this study, we collected domestic short-hair cat admitted to the Veterinary Medicine Teaching Hospital of NCHU from September 2008 to April 2010. Ultrasonographic (USG) examination of kidneys of cats was performed. In addition, polymerase chain reaction (PCR) was used to amplify the PKD1 gene exon 29 of genomic DNA extracted from blood or hair follicle of cats, and sequences of PCR products were further identified by direct sequencing. The prevalence of PKD in short hair cats was investigated. In this study, we collected 179 cats mostly consisting of domestic shorthair cats, combined with 111 cats mostly consisting of Persian and Persian related breed collected by Hsin-Yu Chen. Totally 290 cats were analyzed mostly consisting of domestic shorthair (43.4%), Persian (32.4%), Chinchilla (10%), and American Shorthair (5.9%), and other species (8.3%). All cats were examined by genetic test; among them only 132 cats were screened by ultrasound. The results showed the prevalence of PKD affected domestic shorthair cats diagnosed by USG and gene testing were 12% and 4% respectively. There was no correlation in breeds, age of diagnosis, sex, renal index between the PKD affected cats diagnosed by USG and unaffected cats. However, cats with the PKD1 gene point mutation detected by gene testing related to gender, breed, and the length of hair of cats with significant difference. The male cats, long hair cats and Persian-related breeds have higher risk to PKD than female cats. There were 3 PKD affected cats diagnosed by ultrasound were absent of PKD1 point mutation. The results suggested other mutations may contribute to feline PKD. Moreover, there was only one cat with the PKD1 gene point mutation and didn’t show any cyst in ultrasonography. Perhaps we could explain this result through the “Two-Hit Hypothesis” in human. Other causes such as gene, food intake, and environment may alter the progression of this lethal disease. In conclusion, a paired use of ultrasound and genetic tests should be recommended in order to reach a complete medical condition of cats.

目次

中文摘要 ........................................................................................................................i
英文摘要 .......................................................................................................................ii
目次 ..............................................................................................................................iii
表次 ………………..………………………………………………………………..viii
圖次 ............................................................................................................................. ix
第一章 序言 …………………………………………………………………….…….1
第二章 文獻探討 ……………………………………………………………….…….2
第一節 人類之腎臟囊性疾病 …………………………………………….……...2
一、遺傳性多囊性腎臟異常……………………………………….………2
（一）自體顯性多囊腎病……………………………………………………3
( 1）ADPKD的流行病學及病因學調查………………………………...3
( 2）ADPKD的臨床表現………………………………………………...4
（3）ADPKD的病理學研究……………………………………………...4
（4）ADPKD的診斷……………………………………………………...5
（5）ADPKD與其他腎臟囊腫之區別診斷……………………………...6
a. 單一囊腫…………………………………………………………...6
b. 後天囊性腎病（Acquired cystic kidney disease, ACKD）…………6
c. 結節性硬化症 （Tuberous sclerosis）……………………………...6
d. 自體隱性多囊腎病 （Autosomal recessive polycystic kidney
disease, ARPKD）………………………………………………….7
（二）自體隱性多囊腎病……………………………………………………7
（1）ARPKD的流行病學及病因學調查…………………………………7
（2）ARPKD的臨床表現…………………………………………………7
（3）ARPKD的病理學研究………………………………………………8
（4）ARPKD的診斷………………………………………………………8
（三）囊腫形成的理論：Two-hit model……………………………………..9
（四）與PKD有關的蛋白質………………………………………………...9
（1）Polycystin-1（PC1）………………...………………………………...9
（2）Polycystin-2（PC2）…………………………………………………10
( 3）Fibrosystin / polyductin……………………………………………10
（五）PKDs在細胞學及分子層面的致病機轉……………………………11
（1）囊腫的增生、細胞凋亡（apoptosis）和液體累積…………………11
（2）細胞與細胞及細胞與基質間不當的附著…………………………12
（3） PKD可視為一種纖毛病變（ciliopathy）…………………………13
1. 初級纖毛（primary cilia）的結構…………………………………..13
2. 初級纖毛的功能…………………………………………………...14
a. Mechanosensor…………………………………………………14
b. 細胞週期的調控（Cell cylcle regulator）.......…………………15
3. PKD中訊息傳導途徑的受損……………………………………...16
a. cAMP活化路徑（cAMP-activated pathways）……………….16
b. 血管加壓素（vasopressin）……………………………………17
c. cAMP…………………………………………………………...17
d. Wnt（Wg和Int基因的合併縮寫）的信號傳導（Wnt signaling in PKD）…………………………………………………………...17
e. PCs調控mTOR（mammalian target of rapamycin）複合體….18
（六）PKDs造成腎衰竭的機制……………………………………………20
（七）ADPKD的治療……………………………………………………...20
（1）傳統療法……………………………………………………………..20
（2）對症療法……………………………………………………………..21
1. 疼痛控制…………………………………………………………...21
2. 腎臟感染…………………………………………………………...21
3. 高血壓和左心室肥厚……………………………………………...21
4. 動脈瘤（arterial aneurysms）……………………………………….22
5. 腎結石（nephrolithiasis）…………………………………………..22
6. 血尿（hematuria）…………………………………………………..22
（3）腎取代性療法………………………………………………………..23
1. 透析………………………………………………………………...23
2. 腎臟移植…………………………………………………………...23
（4）特異性療法………………………………………………………….23
1. 表皮生長因子受器（epithlial growth factor receptor, EGFR）酪胺
酸激酶抑制劑（tyrosine kinase inhibitors）………………………23
2. 抑制細胞凋亡……………………………………………………...24
3. 調節cAMP的訊息傳導…………………………………………...24
4. mTOR的抑制………………………………………………………24
5. Cyclin-dependent kinase（CDK）的抑制…………………………..24
6. 刺激PC2調節的鈣離子釋放……………………………………...25
（八）ADPKD的預後…………………………..………………………….25
（九）ADPKD的預防……………………………………………………...25
二、後天囊性腎臟疾病（acquired cystic kidney disease, ACKD）…………...25
﹙一﹚ ACKD的流行病學及病因學調查…………………………………25
﹙二﹚ACKD的病理學研究…………………………………………….26
﹙三﹚ACKD的診斷………………………………………………………26
﹙四﹚ACKD的治療………………………………………………………26
三、腎臟髓質的囊性疾病……………………………………………………..26
（一）腎臟髓質囊腫疾病（medullary cystic disease, MCD）……………...27
（1）MCD的病因學研究………………………………………………..27
（2）MCD的病理學研究………..………………………………………27
（3）MCD的診斷………………………..………………………………27
（4）MCD的治療………………………………..………………………28
1.針對鹽的消耗……………………………………………………….28
2.針對貧血…………………………………………………………….28
（二）髓質海綿腎（medullary sponge kidney, MSK）……………………..28
（1）MSK的病因學及流行病學…………………………………………28
（2）MSK的病理學研究…………………………………………………28
（3）MSK的診斷…………………………………………………………29
（4）MSK的治療…………………………………………………………29
四、單純性囊腫（simple cysts）……………………………………………...…29
（一）單純性囊腫的病因學及流行病學……………………………..……29
（二）單純性囊腫的病理學研究…………………………………………..30
（三）單純性囊腫的診斷…………………………………………………..30
（四）單純性囊腫的治療………………………………………………..…30
第二節 貓之多囊腎病……………………………………………………………31
一、貓PKD的流行病學研究………………………………………………31
二、貓之多囊腎病的病因學研究…………………………………………32
三、貓之多囊腎病的臨床表現……………………………………………33
四、貓之多囊腎病的病理學研究…………………………………………35
（一）囊腫外觀及分佈……………………………………………………..35
（二）上皮細胞增生………………………………………………………..36
（三）Na / K ATPase的異位……………………………………………….36
（四）腎臟外的器官病變………………………………………………..…36
五、貓之多囊腎病的診斷……………………………………………………..…36
（一）超音波檢查…………………………………………………………….36
（二）電腦斷層掃描（Computer Tomography, CT）………………...………37
（三）基因檢測技術………………..……………………………………..…38
六、PKD的治療………………………………………………………………….38
（一）慢性腎衰竭之治療（Treatment of Chronic Renal Failure,
CRF）…………………………………………………………………..38
（1）傳統療法……………………………………………………………..…39
1. 利尿劑………………………………………………………………...39
2. 離子不平衡的矯正……………………………………………...……39
3. 酸鹼不平衡的控制……………………………………………...……39
（2）腎取代性治療………………………………………………………..…40
1. 腹膜透析………………………………………………………...……40
2. 血液透析……………………………………………………...………40
3. 腎臟移植……………………………………………………...………40
（3）飲食療法……………………………………………………………………41
七、多囊腎病造成之腎衰竭的預後評估………………………………………41
八、多囊腎病的移除………………………………………………………..……41
第三章 材料與方法………………………………………………………………..…42
第一節 貓隻多囊腎病之樣本收集………………………………………....……42
第二節 超音波檢測………………………………………………………………42
第三節 DNA萃取…………………………………………………………..……42
一、血液的DNA萃取………………………………………………..……42
二、毛髮的DNA萃取……………………………………………..………43
第四節 聚合酶鍊鎖反應（Polymerase Chain Reaction，PCR）…………..………43
一、PCR引子的設計………………………………………………………43
二、PCR反應………………………………………………………………44
第五節 巢式聚合酶鍊鎖反應（Nested PCR）……………………………………44
一、Nested PCR引子的設計………………………………………...……44
二、Nested PCR反應………………………………………………………44
三、Nested PCR產物確認…………………….……………….…………44
四、Nested PCR產物定序……………………………………………...…45
第六節 統計分析…………………………………………………………...……45
第四章 結果……………………………………………………………………….…46
第一節 貓多囊腎病的流行病學調查………………………………………...…46
一、樣本之基本資料………………………………………………………46
二、PKD超音波檢查結果…………………………………………...……47
﹙一﹚PKD與品種之關係…………………………………………….……48
（二）PKD與被毛長短的關係………………………………….…………50
（三）PKD與性別的關係…………………………………………….……52
（四）PKD與年齡的關係…………………………………………….……52
（五）PKD與BUN、creatinine的關係……………………………..………55
（六）超音波檢查結果與其他變數以chi-square統計分析結果
之總結………………………………………………………………57
（七）單變數邏輯式迴歸分析…………………………………………..…57
三、PKD1的基因突變…………………………………………………….59
（一）聚合酶鍊反應………………………………………………………..59
（二）基因定序結果的判讀………………………………………….……59
（三）PKD1突變與品種的關係……………………………………...……61
（四）PKD1突變與被毛長短的關係………………………………...……65
（五）PKD1突變與性別的關係…………………………………………...66
（六）PKD1突變與BUN、creatinine的關係………………………………66
（七）PKD1突變與其他變數以chi-square統計分析結果
之總結………………………………………………………………68
（八）PKD1突變與超音波檢查結果的關係……………………………...70
（九）PKD1突變與其他變數的單變數logistic分析.......……………...…70
（十）帶有PKD1突變貓隻其年齡與腎臟指數的關係………………....70
（十一）PKD1基因檢測、超音波檢查結果與被毛長短
的關係……………………………………………………………71
（十二）毛髮萃取DNA和血液萃取DNA的確認……………………..…71
（十三）PKD1基因檢測的結果與超音波學檢測結果之間
的關係…………………………………………………………...72
第五章 討論……………………………………………………………………….…74
第一節 貓多囊腎病的流行病學調查……………………………...……………74
一、在台灣中部地區貓隻PKD的盛行率……………………………...…74
二、品種……………………………………………………………………75
三、被毛長短………………………………………………………………76
四、性別……………………………………………………………………76
五、年齡……………………………………………………………………77
六、腎臟指數………………………………………………………………77
第二節 從毛囊抽取DNA應用於貓PKD的診斷……………………….………77
第三節 比較超音波以及PKD1基因檢測用於診斷貓PKD
之間的關係…………………………………………………………....…78
一、超音波檢查……………………………………………………………79
二、PKD1基因檢測……………………………………………….………79
三、超音波檢查與PKD1基因檢測之評估……………………….………79
第四節 利用超音波和基因檢測方法診斷的一致性…………………………...81
參考文獻………………………………………………………………………………82

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