本文關(guān)鍵詞：類脂蛋白沉積癥基因突變及致病機(jī)理研究　出處：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 類脂蛋白沉積癥 ECM1 常染色體隱性遺傳病 基因突變

【摘要】：研究背景類脂蛋白沉積癥(lipoid proteinosis, LP)是一種罕見的常染色體隱性遺傳性皮膚病。由Urbach和Wiethe于1929年首次報道,又稱為Urbach-Wiethe病或皮膚黏膜透明變性。目前本病的病因及沉積物性質(zhì)仍未明確。臨床上其主要表現(xiàn)為皮膚及黏膜不同程度的浸潤、增厚及瘢痕形成,并可累及口腔黏膜、咽喉、神經(jīng)系統(tǒng)及其他內(nèi)臟器官。2002年Hamada首次報道本病是由人類1號染色體2區(qū)1帶(1q21)的細(xì)胞外基質(zhì)蛋白1 (extracellular matrix protein 1, ECM1)基因發(fā)生功能缺失突變引起。ECM1是調(diào)節(jié)表皮分化、真皮膠原和糖蛋白的結(jié)合和調(diào)節(jié)血管生成的關(guān)鍵蛋白。ECM1有10個外顯子,目前總共發(fā)現(xiàn)有51種基因突變,突變多位于外顯子6和外顯子7。研究目的選取類脂蛋白沉積癥兩個家系三名患者及兩名散發(fā)患者進(jìn)行ECM1基因突變相關(guān)研究,尋找ECM1基因外顯子是否存在突變：如果有突變,是否為新發(fā)現(xiàn)的突變位點；如果沒有突變,分析原因。研究方法選取類脂蛋白沉積癥家系中的兩個家系三名患者及兩名散發(fā)患者,采取其血液標(biāo)本,提取血液中DNA。根據(jù)UCSC Genomes提供的ECM1基因全部外顯子信息,為其全部外顯子分別設(shè)計一對引物,PCR擴(kuò)增全部外顯子并進(jìn)行直接測序,使用UCSC BLAT對測序結(jié)果進(jìn)行分析比對,尋找突變位點。研究結(jié)果用10對引物逐一擴(kuò)增類脂蛋白沉積癥一家系兩名患者及其父母、一家系一名患者和兩名散發(fā)患者的ECM1基因全部10個外顯子序列,均得到預(yù)期長短的片段。對PCR產(chǎn)物直接測序,測序結(jié)果進(jìn)行BLAT分析,發(fā)現(xiàn)一種已知突變(純合突變p.C220G)和三個新的突變(純合突變c.508insCTG、復(fù)合雜合突變p.C220G/p.R481X和c.507delT/c.1473delT)。結(jié)論本研究發(fā)現(xiàn)一種已知突變和三種新的突變,這些突變均符合常染色體隱性遺傳。
[Abstract]:Background lipoid proteinosis in patients with lipoprotein deposition. LPP) is a rare autosomal recessive skin disease, first reported by Urbach and Wiethe in 1929. It is also called Urbach-Wiethe disease or hyaline degeneration of skin and mucous membrane. At present, the etiology and sediment properties of this disease are still unclear. The main clinical manifestation of this disease is infiltration of skin and mucous membrane to different degrees. Thickening and scar formation, and can involve oral mucosa, throat. Nervous system and other visceral organs. In 2002, Hamada first reported that the disease is an extracellular matrix protein (ECM) 1 (. Extracellular matrix protein 1. ECM1 is the key protein to regulate the differentiation of epidermis. There are 10 exons in ECM1, which is the key protein to regulate the binding of dermal collagen and glycoprotein and the regulation of angiogenesis. A total of 51 mutations have been identified. Objective to study the relationship between ECM1 gene mutation and ECM1 gene mutation in two families of two families of lipoprotein deposition, three patients and two sporadic patients. To find out if there is mutation in exon of ECM1 gene: if there is mutation, whether it is a newly discovered mutation site; If there was no mutation, the causes were analyzed. Methods three patients and two sporadic patients from two families with lipoprotein deposition were selected and their blood samples were taken. According to the information of all exons of ECM1 gene provided by UCSC Genomes, a pair of primers were designed for all exons. All exons were amplified by PCR and sequenced directly. UCSC BLAT was used to analyze and compare the sequencing results. The results showed that 10 pairs of primers were used to amplify one by one two patients and their parents of a family of patients with lipoprotein deposition. All 10 exons of ECM1 gene from a family of one patient and two sporadic patients were sequenced with expected length. The PCR products were sequenced directly and the results were analyzed by BLAT. A known mutation (homozygous mutation p.C220G) and three new mutations (homozygous mutation c.508insCTG) were found. Compound heterozygous mutations p.C220G / p.R481X and c.507delT / c.1473delT.Conclusion one known mutation and three new mutations were found in this study. These mutations are autosomal recessive inheritance.
【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】：2015
【分類號】：R758.4

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本文編號：1378652