先天性心脏病及白内障遗传学研究

发布时间：2018-06-20 09:42

本文选题：先天性心脏病 + 先天性白内障　；参考：《北京协和医学院》2012年硕士论文

【摘要】：研究目的:先天性心脏病(Congenital Heart Defect,CHD)是小儿先天性畸形中最为常见的一种,严重危害着儿童健康及生命,消耗大量的、有限的公共医疗资源。通过对CHD的发生机理的认识、研究,掌握心脏病的致病机制,早发现、早诊断、早治疗,对于降低先天性心脏病患者的死亡率和出生率具有非常重要的意义。本论文第一部分主要使用分子遗传学技术手段,从基因变异角度,对CHD的病因和发病机制进行研究。白内障(Cataract)是指眼睛内晶状体及晶状体囊部分或全部混浊。在世界范围内白内障是致盲的主要病因,我国发病率为0.04%,欧美国家发病率在0.01-0.06%之间,现在世界上大约有1800万失明患者是由于白内障致盲的,大多数发生在非洲和亚洲国家。本研究第二部分通过筛查先天性遗传白内障相关的遗传变异位点,来研究相关变异位点与白内障发生的致病机理,探究眼晶状体分化、发育及成熟的生物学过程,初步分析基因型与表型、突变与蛋白性质改变、蛋白性质改变与疾病发生的分子生物学机制。研究方法:通过功能候选,选择与心脏发育相关的候选基因HEY2,及与眼和晶状体发育相关的CRYAA,CRYAB,CRYBA1,CRYBB2,CRYGC,CRYGD,CRYGS,GJA3,GJA8基因,分别在散发先天性心脏病病例和先天性白内障家系中,通过对编码区及外显子剪接位点处直接测序,筛查变异位点,使用应用生物信息学手段分析相关变异位点,对有价值的变异位点构建体外表达系统,初步研究其蛋白质功能。结果与结论:在先天性心脏病患者中,筛查HEY2基因未发现相关变异位点。先天性白内障家系中,筛查CRYBB2基因发现11个变异位点,其中在Cat-02家系中发现rs74315489的截断变异位点;筛查CRYGC基因,在Cat-01家系中发现ss325992558导致NP_066269p.G129C错义突变;筛查CRYGD基因,发现3个变异位点,分别是 ss290489929,ss290489935,ss290489940;筛查 GJA3,CRYA A,CRYB和CRYBA1基因分别发现 NP_068773:p.Leu299Met,ss290489937,rs11603779和ss290489938变异位点,分析发现可能是起始变异。本论文还对发现的同义变异位点进行密码子偏爱分析,并研究其对转录因子结合效率的影响,从遗传学角度为阐述先天性白内障的病理机制提供了重要的参考。
[Abstract]:Objective: Congenital Heart defect (CHD) is one of the most common congenital malformations in children, which seriously endangers the health and life of children and consumes a large amount of limited public medical resources. Through understanding and studying the pathogenesis of CHD, mastering the pathogenesis of heart disease, early detection, early diagnosis and early treatment, it is of great significance to reduce the mortality and birth rate of patients with congenital heart disease. In the first part of this thesis, the etiology and pathogenesis of CHD were studied from the perspective of gene variation by means of molecular genetics. Cataract refers to partial or complete opacity of the intraocular lens and lens capsule. Cataract is the main cause of blindness in the world. The incidence of cataract is 0.04% in China and 0.01-0.06% in Europe and the United States. At present, there are about 18 million blind patients in the world due to cataract blindness, most of which occur in African and Asian countries. In the second part of this study, by screening genetic variation sites associated with congenital hereditary cataract, we studied the pathogenesis of cataract and the biological process of lens differentiation, development and maturation. The molecular biological mechanism of genotype and phenotype, mutation and protein property change, protein property change and disease occurrence were preliminarily analyzed. Methods: according to the functional candidates, the candidate gene HEY2 related to cardiac development and CRYAAA CRYABA CRYBA 1 and CRYBB2 CRYGCU CRYGDU CRYGSGJA3 GJA8 gene were selected in a family of sporadic congenital heart disease and congenital cataract, respectively. The coding region and exon splicing site were directly sequenced and the mutation sites were screened. Bioinformatics was used to analyze the relevant mutation sites. The expression system was constructed for the valuable mutation sites and its protein function was preliminarily studied. Results & conclusion: in patients with congenital heart disease, no mutation sites were found in the screening of HEY2 gene. In pedigrees with congenital cataract, 11 mutation sites were found in CRYBB2 gene, among them, truncated mutation sites of rs74315489 were found in Cat-02 families, and ss325992558 was found in Cat-01 pedigree, which resulted in NP066269p.G129C missense mutation, and CRYGD gene was screened. Three mutation sites were found, which were ss290489935, and GJA3G, CRYA, CRYB and CRYBA1, respectively. NP068773: p.Leu299Metss290489937 rs11603779 and ss290489938 mutation were found. The codon preference analysis of synonymous mutation sites and the effect of codon preference on the binding efficiency of transcription factors provide an important reference for the elucidation of the pathological mechanism of congenital cataract from the perspective of genetics.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R725.4;R776.1

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