臺灣博碩士論文加值系統

腎原性尿崩症是一種罕見的性聯遺傳隱性疾病 (MIM No. 304800)， 主要是因為抗利尿激素的作用異常時， 而導致多尿、多渴和脫水的尿崩症病徵出現。 在 1990 年左右， 研究發現位於腎小管遠端的 V2 受體發生缺失， 是造成先天腎原性尿崩症的主因。 V2 受體基因長約 2 Kb， 而 V2 受體本身為 Gs 蛋白結合受體， 在構形上具 7 個穿膜區域， 負責訊號的傳導。 由於 V2 受體基因已經被選植並完整地定序， 因此非常有利於分子遺傳學上的研究。 同時從案例報告當中得知， V2 受體基因突變種類包含所有可能的核?酸突變型式以及大片段的插入或缺失； 且發生的位置在細胞膜內、外和細胞膜上都有可能， 顯示腎原性尿崩症在基因變異上具有多樣性。
針對整個AVPR2基因做自動高溫核酸定序之後， 我們在所發現的兩個先天腎原性尿崩症家庭， 分別在第二外顯子找到了一個 c.316 C>T 的核?酸變異， 使精胺酸被半胱胺酸所取代； 和另一 c.861 C>A 的核?酸變異， 會造成苯丙胺酸變成白胺酸。 同時， 在第三外顯子上有一個 c.927 A>G 的核?酸變異， 這個變異並沒有造成胺基酸的改變， 仍為白胺酸， 且在正常人的 DNA 中亦會出現。 c.316 C>T 突變和 c.927 A/G 多形性變異已經有文獻報導， 而未曾有 c.861 C>A 的案例報告。 因為患病家族中有病徵出現的兩兄弟同樣擁有此一基因變異， 而且在 AVPR2 基因編碼序列的其餘位置並沒有其他核?酸變異， 同時在 100 個正常人的對偶基因中並沒發現這個變異， 推測這是先天腎原性尿崩症中新發現的突變點。 統計在中國人 c.927 A/G 多形性的頻率， 發現對偶基因 A 出現的頻率為 29 %， 而偶基因 G 出現的頻率則為 71 %， 此項結果與日本所發表的數據十分雷同， 而與西方人不同。 在 COS-7 細胞轉染的功能表現實驗中發現， 即使是在高濃度的 AVP [10-6M] 作用時， c.316 C>T 和 c.861 C>A 的 V2 受體蛋白接受 AVP 刺激產生 cAMP 的功能， 也只能達到野生型的 17~28 % 和 41~47 % 的程度， 証明此兩個突變體的 V2 受體蛋白的確在訊號傳導上有所缺失，是為致病的突變。

Nephrogenic Diabetes Insipidus (NDI) is a rare X-linked recessive renal disorder (MIM No. 304800) due to resistance to antidiuretic action of arginine vasopression (AVP) hormone. NDI is characterized with clinical symptoms of polyuria, polydipsia and dehydration. Previous studies have demonstrated that the NDI is caused by the defects of vasopressin 2 receptor (V2R) in renal tubules. The V2R belongs to the family of G-protein coupled receptors that contain seven distinct transmembrane domains. The gene encoding V2R has been cloned and sequenced, which facilitates the genetic study of NDI at molecular level. Several gene defects of NDI have been identified, including various point mutations, insertion and deletions, suggesting genetic heterogeneity of NDI.
We have identified two families with clinical diagnosis of NDI. By using the polymerase chain reaction (PCR)-based sequencing, we investigated three protein-coding exons and their flanking introns of V2R gene of these families. A C-to-T transition at nucleotide 316, a C-to-A transversion at nucleotide 861 and an A-to-G polymorphism site at nucleotide 927 were identified. These variants predict an Arg substitution at codon 106 by Cys, a Phe substitution at codon 287 by Leu and an unchanged Leu at codon 309 of V2R, respectively. The frequences of G and A alleles in normal Chinese population at the nucleotide 927 polymorphism site were found to be 0.71 and 0.29, respectively, which is similar to that of Japanese but different from that of Scandinavian. Although the molecular variant at codon 106 and the polymorphism site at codon 309 have been reported. The variant at codon 287 has not been reported previously, and was not found in 100 normal Chinese alleles, suggesting that this c.861 C>A molecular variant might be a novel mutation of V2R causing NDI. Expression of these variant forms of V2R gene in COS-7 cell also showed that these two molecular mutations at nucleotide 316 and 861 had decreased their ability to accumulate cAMP in response to AVP [10-6M] stimulation significantly.

壹、 中文摘要1
貳、 英文摘要2
參、 緒論
一、 尿崩症的成因與臨床症狀 3
二、 尿崩症的分類4
三、 腎原性尿崩症的病因 6
四、 先天腎原性尿崩症的病理生理學 6
五、 先天腎原性尿崩症的臨床診斷與治療 7
六、 先天腎原性尿崩症的分子生物遺傳分析 8
七、 研究目的10
肆、 材料與方法
一、 檢體來源與樣本的製備11
二、 腎原性尿崩症患病家族 AVPR2 基因分子變異之分析13
三、 正常與突變之 AVPR2 cDNA 的製備16
四、 猿猴腎臟細胞 (COS-7 cell) 的轉染作用18
五、 V2 受體在 COS-7 細胞上表現位置之偵測19
六、 正常與突變之 V2 受體 cAMP 表現能力測定20
伍、 結果
一、 腎原性尿崩症患病家族 AVPR2 基因分子變異之分析21
二、 腎原性尿崩症病患家族血液和尿液的生化檢驗分析25
三、 腎原性尿崩症 AVPR2 基因多形性頻率統計26
四、 V2 受體在 COS-7 細胞上表現位置之偵測27
五、 正常與突變之 V2 受體 cAMP 表現能力測定29
陸、 討論
一、 AVPR2 基因分子變異之分析32
二、 限制?剪輯反應及家族遺傳分析33
三、 AVPR2 基因多形性頻率統計33
四、 血液和尿液的生化檢驗分析34
五、 V2 受體在 COS-7 細胞上表現位置之偵測35
六、 正常與突變之 V2 受體 cAMP 表現能力測定36
七、 研究的貢獻與未來可繼續的研究方向37
柒、 參考文獻
一、 先天腎原性尿崩症的簡介、檢驗報導與基因分析39
二、 國人對於尿崩症的研究41
三、 先天腎原性尿崩症案例的 AVPR2 基因突變相關報導41
四、 AVPR2 基因突變與 V2R 蛋白質功能的相關研究44
五、 其他參考資料45
捌、 附件
附件一、AVPR2 gene sequence47
附件二、AVPR2 mutation list49
附件三、血液和尿液的生化檢驗分析結果53
附件四、Genomic DNA Isolation57
附件五、Polymerase Chain Reaction (PCR) 60
附件六、高溫循環核酸定序法62
附件七、Extraction and Purification of Plasmid DNA65
附件八、Site-Direct Mutagenesis68
附件九、勝任細胞製備與轉化作用71
附件十、冷凍細胞活化72
附件十一、細胞繼代培養73
附件十二、黴漿菌污染測試:DNA螢光染色法74
附件十三、基因轉殖法 (Transfection) - liposome77
附件十四、b-Galactosidase Assay79
附件十五、Immunofluorescence Stain81
附件十六、Protein Determination by Lowry Method83
附件十七、cAMP Assay84

一、 先天性腎原性尿崩症的簡介、檢驗報導與基因分析
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二、國人對於尿崩症的研究
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三、先天性腎原性尿崩症案例的AVPR2 基因突變相關報導
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四、AVPR2基因突變與V2R蛋白質功能的相關研究
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