臺灣博碩士論文加值系統

遺傳性腎小管疾病的臨床表現為肌肉無力、運動不耐受性、多尿、抽搐、身材矮小、骨頭病變等，生化檢驗可以電解質或酸鹼不平衡如低血鉀、低血鈣、代謝性酸中毒等特徵，遺傳模式可以是自體顯性、隱姓或性聯隱性。因為大部份的遺傳模式為自體隱性遺傳，再加上初期症狀並不明顯，因此通常延後診斷；此類疾病若沒有及時發現，可能造成生長遲緩、腎功能衰竭甚至死亡。在過去的數年中，我們診斷了許多腎小管疾病，包括吉特曼症候群、巴特氏症候群、以范康尼氏症候群表現的LOWE症候群、Dent’s 疾病、粒線體疾病、體隱性鈉磷通道疾病、家族性低血鎂高尿鈣腎髓質鈣化症、腎性尿崩症及體隱性腎小管發育不全等，雖然部份病人在診斷後給予適當的治療，病情可以獲得改善，但是關於此類病同之基因缺陷導所導致疾病的機轉仍未被詳細的研究。
在第一章，我們報告一位因新的維生素D接受體基因缺陷(R343H)導致維生素D抗性佝僂症合併禿髮的兒童，活性維生素D藉由與維生素D接受體結合，作用在腎臟遠曲小管的鈣離子通道TRPV5，促進鈣離子的重吸收，此病童臨床表現為低血鈣、高血中活性維生素D、佝僂症及禿髮，給予大量的口服鈣離子及活性維生素D的補充，病童的低血鈣及佝僂症有改善但禿髮仍然持續; 由於維生素D接受體基因缺陷(R343H)是一新的突變點及此點位於與RXR的結合點且過去很少被並發表，因此我們試圖釐清在此一新發現的維生素D接受體基因缺陷對維生素D誘導的基因表現的影響及其可能的致病機轉。
在第二章中，我們研究台灣吉特曼症候群病人的基因型及表現行和長期追蹤的預後。吉特曼症候群導因於solute carrier family 12, member 3 (SLC12A3)基因突變導致腎臟遠區小管的Na+-Cl- contrasporter失能，病人的臨床表現為肌肉無力、多尿、抽筋、生長遲緩等，生化檢驗呈現低血鉀、低血鎂、低尿鈣以及代謝性鹼中毒，我們過去的研究發現約有百分之三的台灣人為基因缺陷帶因者，這顯示吉特曼症候群在台灣並非少見疾病; 再者，關於吉特曼症候群的基因型及表現型的關連性研究目前不多; 近來，有一些病例報告顯示吉特曼症候群的病人併發慢性腎疾病及糖尿病，但關於此類病人的長期追蹤研究甚少且亞洲並無文獻報告。
在第三章，遺傳性腎小管發育不良是一種自體隱性遺傳疾病，病因爲基因缺陷導致腎素血管張力素系統功能受損，目前我們總共診斷四例個案，我們基於前面的研究基礎，對此病進行功能性分析研究。

Inherited renal tubular disorders are characterized by muscle weakness, exertional intolerance, polyuria, convulsion, short stature, and rickets during childhood. The main biochemical abnormalities include dysnatremia, dyskalemia, dyscalcemia, metabolic acidosis and metabolic alkalosis. The modes of inheritance could be autosomal recessive, autosomal dominant, X-linked recessive or X-linked dominant. Because the major inheritance is autosomal recessive and the initial presentations are insidious, it is difficult to make an early diagnosis of inherited renal tubular disorders. However, it leads to growth retardation, renal failure and even death from delayed diagnosis or treatment.
In recent years, we have diagnosed several inherited renal tubular disorders including Gitelman’s syndrome, Bartter’s syndrome, renal fanconi syndrome results from LOWE syndrome, Dent’s disease, and mitochondrial disorder, familial hypomagnesemia hypercalciuria nephrocalcinosis, nephrogenic diabetes insipidus, and autosomal recessive renal tubular dysgenesis by molecular analysis. The improvement of clinical conditions of most of our patients was achieved after timely diagnosis and appropriate treatment.
In chapter 1, we presented a child with hereditary vitamin D-resistant rickets (HVDRR) caused by a novel mutation on RXR domain of vitamin D receptor gene. This child exhibited hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, increased serum 1,25-dihydroxyvitamin D3, rickets and alopecia. Although patients with mutations in different binding domains have been shown to exhibit distinct and variable severity of phenotypes, the study of the VDR mutant on RXR-binding domains remains limited. Therefore, we conducted a functional study was performed to explore the molecular mechanism in vitro to aid in understanding the pathogenesis of HVDRR.
In chapter 2, mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter on the apical membrane of distal convoluted tubule lead to Gitelman’s syndrome. We attempted to investigate the genotype, phenotype and follow-up of Taiwanese with Gitelman syndrome.
In chapter 3, Autosomal recessive renal tubular dysgenesis is caused by genetic defects on AGT, REN, ACE or AT1R and is characterized by absence or poor-differentiated proximal convoluted tubules. Recently, we firstly identified five patients of ARRTD caused by identical homozygous large deletion of AGT gene from four unrelated families within 3 year in Taiwan. We will explore the pathogenic role of roles of our defected AGT on the development of renal tubular dysgenesis.

口試委員會審定書 ………………………………………………………………1
誌謝 ………………………………………………………………………………2
中文摘要 ………………………………………………………………………… 3
英文摘要 ………………………………………………………………………… 4
博士論文內容
Chapter 1 …………………………………………………………………………5
緒論 (Introduction) ……………………………………………………………6-10
研究方法與材料 (Material and Methods) ……………………………………11-16
結果 (Results) …………………………………………………………………17-21
討論 (Discussions) ……………………………………………………………22-26
表1 ……………………………………………………………………………27
圖1~圖7 ………………………………………………………………………28-34
Chapter 2 ………………………………………………………………………35
緒論 (Introduction) …………………………………………………………36-38
研究方法與材料 (Material and Methods) ……………………………………39-41
結果 (Results) ………………………………………………………………42-44
討論 (Discussions) ……………………………………………………………45-47
表1 ……………………………………………………………………………48
圖1 ……………………………………………………………………………49
Chapter 3未來研究展望 (Future work) ………………………………………50
緒論 (Introduction) …………………………………………………………51-56
表1 …………………………………………………………………………57
圖1 ~圖3 ……………………………………………………………………58-60
參考文獻 (References) …………………………………………………………61-75

附錄：列出個人在碩博士班修業期間所發表之相關論文清冊 ……………76-78

Chapter 1.
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30.Malloy, P.J., Xu, R., Peng, L., Clark, P.A. & Feldman, D. A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D–resistant rickets without alopecia. Mol Endocrinol. 16: 2538–2546 (2002).
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Chapter 2.
1.Gitelman HJ, Graham JB, Welt GL. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:211-235 (1966).
2.Simon DB et al. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12:24-30 (1996).
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