类脂蛋白沉积症基因突变及致病机理研究

发布时间：2018-01-04 13:15

本文关键词：类脂蛋白沉积症基因突变及致病机理研究　出处：《北京协和医学院》2015年博士论文　论文类型：学位论文

【摘要】：研究背景类脂蛋白沉积症(lipoid proteinosis, LP)是一种罕见的常染色体隐性遗传性皮肤病。由Urbach和Wiethe于1929年首次报道,又称为Urbach-Wiethe病或皮肤黏膜透明变性。目前本病的病因及沉积物性质仍未明确。临床上其主要表现为皮肤及黏膜不同程度的浸润、增厚及瘢痕形成,并可累及口腔黏膜、咽喉、神经系统及其他内脏器官。2002年Hamada首次报道本病是由人类1号染色体2区1带(1q21)的细胞外基质蛋白1 (extracellular matrix protein 1, ECM1)基因发生功能缺失突变引起。ECM1是调节表皮分化、真皮胶原和糖蛋白的结合和调节血管生成的关键蛋白。ECM1有10个外显子,目前总共发现有51种基因突变,突变多位于外显子6和外显子7。研究目的选取类脂蛋白沉积症两个家系三名患者及两名散发患者进行ECM1基因突变相关研究,寻找ECM1基因外显子是否存在突变：如果有突变,是否为新发现的突变位点；如果没有突变,分析原因。研究方法选取类脂蛋白沉积症家系中的两个家系三名患者及两名散发患者,采取其血液标本,提取血液中DNA。根据UCSC Genomes提供的ECM1基因全部外显子信息,为其全部外显子分别设计一对引物,PCR扩增全部外显子并进行直接测序,使用UCSC BLAT对测序结果进行分析比对,寻找突变位点。研究结果用10对引物逐一扩增类脂蛋白沉积症一家系两名患者及其父母、一家系一名患者和两名散发患者的ECM1基因全部10个外显子序列,均得到预期长短的片段。对PCR产物直接测序,测序结果进行BLAT分析,发现一种已知突变(纯合突变p.C220G)和三个新的突变(纯合突变c.508insCTG、复合杂合突变p.C220G/p.R481X和c.507delT/c.1473delT)。结论本研究发现一种已知突变和三种新的突变,这些突变均符合常染色体隐性遗传。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R758.4

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