本文選題：單基因糖尿病 + 青少年起病的成人型糖尿病��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年博士論文

【摘要】：目的 單基因糖尿病(monogenetic diabetes)是指由單個基因突變導(dǎo)致的糖尿病,以單基因模式遺傳,約占全部糖尿病患者的1%-2%,其中最常見的類型為青少年起病的成人型糖尿病(maturity onset diabetes of the young, MODY)。MODY目前已知13種致病基因,分為13種亞型,功能均與胰島B細胞發(fā)育、凋亡、功能、葡萄糖代謝和胰島素相關(guān),如INS、HNF1A、GCK等。MODY的臨床表型、預(yù)后、治療方案和胰腺外表型與其致病基因相關(guān),因此基因診斷對于MODY的治療、預(yù)后及家系中患病成員的診治具有非常重要的指導(dǎo)意義。至今仍有10%-20%的臨床表現(xiàn)典型的MODY患者未能檢測到致病基因。因此,利用新的技術(shù)手段探索新發(fā)致病基因具有重要意義。 目標區(qū)域測序技術(shù)使基因檢測不再局限于單個片段的局部檢測,它可以針對眾多已知的或研究者感興趣的目的基因進行大范圍的檢測,與全外顯子測序技術(shù)相比,它價格低廉,產(chǎn)生的數(shù)據(jù)量少,目的性明確,已經(jīng)成為單基因疾病,甚至復(fù)雜多基因疾病研究領(lǐng)域的一種成熟的基因檢測手段。本研究旨在利用目標區(qū)域測序,針對胰島B細胞功能及能量代謝通路中的重要基因進行單基因糖尿病未知致病基因的探索。 對象和方法 1.挑選病例 我們首先用Sanger測序法根據(jù)本中心45例單基因糖尿病家系的臨床表型進行相應(yīng)致病基因(GCK/HNF1A/HNF4A/KCNJ11)的測序分析,排除了已知致病基因家系12例。從剩余家系中選擇遺傳規(guī)律明顯且癥狀典型的32例患者進行目標區(qū)域測序。 2.數(shù)據(jù)分析 單基因糖尿病的己知致病基因均與胰島B細胞功能及能量代謝相關(guān),推測未知致病基因也具有相似的基因功能。針對檢測到的、符合家系遺傳規(guī)律的少見突變的基因及位點逐個進行分析,搜集文獻,再進一步整合得出可能的致病基因。 3.驗證 在NCBI上進行候選基因的功能和蛋白結(jié)構(gòu)的檢索,且完善家系成員與此基因的相關(guān)臨床資料和生化檢查。 結(jié)果 檢索并逐個分析32例家系患者所得的少見基因突變,根據(jù)位點突變蛋白功能預(yù)測和基因功能等相關(guān)文獻報導(dǎo)進行排除,最終確定UCP3可能是MODY的一種新的致病基因。該基因編碼線粒體內(nèi)膜上的解偶聯(lián)蛋白,控制離子轉(zhuǎn)運,維持能量梯度和質(zhì)子濃度差,與脂肪酸在線粒體中的氧化調(diào)節(jié)相關(guān)。有關(guān)聯(lián)性分析發(fā)現(xiàn)其突變與兒童早發(fā)性肥胖和成人肥胖、高脂血癥、2型糖尿病相關(guān)。 結(jié)論 本研究旨在通過目標區(qū)域測序?qū)ふ覇位蛱悄虿〉奈粗虏』?通過分析45例糖尿病家系找到了候選基因UCP3,它與能量代謝相關(guān),但仍需進一步驗證。本研究初步探索了目標區(qū)域測序在單基因疾病中的應(yīng)用和數(shù)據(jù)統(tǒng)計方法,證實了其在單基因疾病領(lǐng)域的研究重要性。
[Abstract]:Purpose Monogenic diabetes mellitus refers to diabetes caused by a single gene mutation, which is inherited in a single gene pattern. About 1- 2% of all patients with diabetes, the most common type of disease is adult diabetes maturity onset diabetes of the young, MODY).MODY, the most common type is the adult diabetes maturity onset diabetes of the young, MODY).MODY, which is known to cause 13 kinds of genes, including 13 subtypes, all of which are related to the development, apoptosis and function of islet B cells. Glucose metabolism is associated with insulin, such as the clinical phenotype, prognosis, therapeutic regimen and appearance of pancreas of INSN HNF1A, GCK, et al., so gene diagnosis is associated with the treatment of MODY. The prognosis and the diagnosis and treatment of the family members are of great significance. So far, 10-20% of MODY patients with typical clinical manifestations have failed to detect pathogenic genes. Therefore, it is of great significance to explore new pathogenic genes by means of new techniques. The target region sequencing technique does not limit the gene detection to the local detection of a single fragment. It can be used to detect a large range of known or interesting target genes. Compared with total exon sequencing technology, it is cheaper than the whole exon sequencing technology. Because of its small amount of data and clear purpose, it has become a mature method for gene detection in the field of single gene diseases and even complex polygenic diseases. The purpose of this study was to explore the unknown genes involved in single gene diabetes mellitus (MDM) by using target region sequencing to identify the important genes in the islet B cell function and energy metabolism pathway. Objects and methods 1. Selection of cases We first analyzed the corresponding pathogenic gene (GCK / HNF1A / HNF4A / KCNJ11) by Sanger sequencing according to the clinical phenotype of 45 monogenic diabetic families in our center, and excluded 12 families with known pathogenetic genes (GCK / HNF1A / HNF4A / KCNJ11). The target regions were sequenced from 32 patients with obvious inheritance and typical symptoms from the remaining families. 2. Data analysis The known pathogenetic genes of single gene diabetes are related to the function of islet B cells and energy metabolism. It is inferred that unknown pathogenetic genes have similar gene functions. The rare mutation genes and loci were analyzed one by one and the literature was collected and the possible pathogenic genes were further integrated. 3. Verification The function and protein structure of candidate gene were searched on NCBI, and the clinical data and biochemical examination of family members were improved. Result The rare gene mutations obtained from 32 pedigrees were retrieved and analyzed one by one. According to the functional prediction of locus mutant protein and gene function, UCP3 may be a new pathogenetic gene of MODY. The gene encodes uncoupling proteins in mitochondrial intima, controls ion transport, maintains low energy gradient and proton concentration, and is related to the oxidation regulation of fatty acids in mitochondria. The mutation was associated with early childhood obesity, adult obesity, hyperlipidemia and type 2 diabetes. Conclusion The purpose of this study was to search for unknown genes of single gene diabetes by sequencing the target region. The candidate gene UCP3 was found by analyzing 45 diabetic families. UCP3 is related to energy metabolism, but it still needs to be further verified. In this study, the application and statistical method of target region sequencing in single gene diseases were preliminarily explored, and its importance in the field of single gene diseases was confirmed.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R587.1;R440

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