药物依赖易感基因的关联分析和孤独症易感基因的突变筛查
发布时间：2018-09-12 07:42
【摘要】：甲基化CpG结合蛋白2(Methyl-CpG binding protein2, MECP2)是一种已知的转录抑制因子,带有两个特征性的功能域：甲基化DNA结合域和转录抑制结构域,具有调节转录、改变染色体构象、参与RNA剪切等多种功能,在神经发育过程中起着重要的作用。大量研究表明,MECP2基因突变与Rett综合征、孤独症、智力低下等多种神经发育性疾病相关,现已成为研究疾病易感基因的基因型与人类多种神经发育性疾病之间关系的一个热点。 药物成瘾已经成为国内外突出的社会和医学问题。长期药物成瘾不仅损害患者身心健康,也会容易传染艾滋病、诱发犯罪等,是严重的社会不稳定因素。药物成瘾(drug addiction)是一种以失去自我控制、强迫性反复用药为主要特征的慢性复发性脑疾病,它是遗传因素和环境因素共同作用的结果。家系调查发现,药物依赖的遗传率高达54%。人们对遗传因素在药物依赖中的作用关注度逐渐升高。近年来,对药物依赖的研究已取得了相当大的进展,但依赖的机制仍未完全阐明,不少治疗方法虽起到一定的作用,但总体疗效欠佳。只有彻底搞清成瘾的生物学机制；才能找到有效的治疗和预防方法。有研究表明MECP2基因与BDNF (Brain-derived neurotrophic factor)基因为药物依赖的易感基因,但现有的研究多数是生理学和形态学上的,而基因多态性与药物依赖之间的关联研究尚无报道。 本课题探讨了MECP2基因和BDNF基因多态性与海洛因依赖的关联性,以便于能够更好的了解海洛因成瘾的遗传机制。对32名健康对照者的MECP2基因和BDNF基因进行测序分析,找到SNP位点；在331名海洛因依赖者和325名健康对照者中,用SNaPshot技术进行基因分型；根据调查量表信息将病例组中的男性患者分为高低剂量两组；用Haploview4.2及SPSS15.0软件分析SNP与药物依赖的相关性。结果发现MECP2基因rs2075597、rs61751363和rs189253298的基因型及等位基因频率在海洛因依赖组与对照组中分布差异不显著,而rs189253298基因型频率在低剂量组和高剂量组中的分布差异显著,有统计学意义(P=0.012)。这表明MECP2基因的rs189253298多态性位点与海洛因依赖者成瘾后每天海洛因的使用量相关,携带有G等位基因的个体每天使用的海洛因量较低,是一个保护因素。BDNF基因的rs11030102的等位基因频率在海洛因依赖组与对照组中分布差异显著,有统计学意义(P0.05)。rs11030101和rs7124442基因型频率在低剂量组和高剂量组中的分布差异显著(P=0.033,P=0.032)。表明BDNF基因的rs11030102多态性位点与海洛因依赖相关,rs11030101和rs7124442多态性位点与海洛因依赖者成瘾后每天海洛因的使用量相关,携带有T、G等位基因的个体每天使用的海洛因量较低,是一个保护因素。 孤独症一般起病于婴幼儿时期,是一种以语言障碍、社交障碍和刻板狭隘的兴趣为基本临床特征的广泛性发育障碍(Pervasive developmental disorder,PDD),常常合并精神发育迟滞、感知觉和情绪等方面异常。严重影响儿童身心发展。目前认为它是由遗传、神经生化、病毒感染、免疫系统等多种因素所引起的,其中遗传因素在孤独症的发病中占有重要的地位。近年来的流行病学研究发现孤独症的患者数正逐年增加。一般孤独症的男性患者多于女性患者,二者的比例接近4：1,这表明孤独症的发病原因可能与X染色体相关,另外孤独症和Rett综合征均属于广泛性发育障碍(PDD),二者的许多临床表现比较相似。据此人们推测孤独症与RTT可能具有某些共同的发病机制。而MECP2基因是目前RTT已经确认的主要致病基因,于是MECP2基因的突变在孤独症中的作用成为研究的热点。本课题在288个孤独症患者与384个正常对照者样本中对MECP2基因进行测序,发现了5个错义突变(T197M、G232A、H371R、E394K、G428S),对其进行功能研究发现,这五个突变并不影响MECP2蛋白的正确定位,而Real-Time PCR的结果表明T197M、G232A是比较严重的转录抑制功能突变,而另外三个并不是完全的转录抑制突变,可能与其他功能有关。另外我们还在288个孤独症患者中检测了MECP2基因拷贝数的变异,在两个孤独症患者中检测到MECP2基因存在一个拷贝数的缺失。这表明MECP2基因的突变与孤独症之间存在一定的关联性。
[Abstract]:Methyl-CpG binding protein 2 (MECP2) is a known transcription inhibitor with two characteristic functional domains: methylated DNA binding domain and transcription inhibitory domain. It plays an important role in neural development by regulating transcription, altering chromosomal conformation, and participating in RNA splicing. A large number of studies have shown that MECP2 gene mutations are associated with Rett syndrome, autism, mental retardation and other neurodevelopmental disorders, and have become a hot spot in the study of the relationship between the genotypes of disease susceptibility genes and various human neurodevelopmental diseases.
Drug addiction has become a prominent social and medical problem both at home and abroad. Long-term drug addiction is not only harmful to the physical and mental health of patients, but also susceptible to infection of AIDS, crime and so on. It is a serious social instability factor. Drug addiction is a chronic relapse characterized by loss of self-control and compulsive repeated use of drugs. Family studies have found that the heritability of drug dependence is as high as 54%. Attention to the role of genetic factors in drug dependence has gradually increased. In recent years, considerable progress has been made in the study of drug dependence, but the mechanism of dependence has not been fully elucidated. Fewer treatments play a role, but the overall effect is poor. Only by thoroughly understanding the biological mechanism of addiction can effective treatment and prevention be found. Some studies have shown that MECP2 gene and BDNF (Brain-derived neurotrophic factor) gene are susceptible genes for drug dependence, but most of the existing studies are physiological and morphological. In fact, the association between genetic polymorphism and drug dependence has not been reported.
In order to better understand the genetic mechanism of heroin addiction, the association between the polymorphisms of MECP2 and BDNF genes and heroin dependence was explored. The SNP loci of MECP2 and BDNF genes were sequenced and analyzed in 32 healthy controls, and the SNaPshot technique was used in 331 heroin addicts and 325 healthy controls. The results showed that the genotype and allele frequencies of MECP2 gene rs2075597, rs61751363 and rs189253298 were found in heroin dependent group and control group. The results showed that the rs189253298 polymorphism of MECP2 gene was associated with daily heroin use in heroin addicts, and the individuals with G allele used the sea every day. The allele frequencies of BDNF gene rs11030102 were significantly different between heroin addicts and controls (P 0.05). The genotype frequencies of rs11030101 and rs7124442 were significantly different between low dose group and high dose group (P = 0.033, P = 0.032). The rs11030101 and rs7124442 polymorphisms were associated with daily heroin use in heroin addicts. Individuals with T and G alleles had lower daily heroin use, which was a protective factor.
Autism, which usually begins in infancy, is a pervasive developmental disorder (PDD) characterized by language disorders, social disorders and stereotyped narrow interests. It is often associated with mental retardation, sensory and emotional abnormalities. It seriously affects the physical and mental development of children. Genetic factors play an important role in the pathogenesis of autism. Epidemiological studies in recent years have found that the number of autistic patients is increasing year by year. The etiology of autism may be related to X chromosome. In addition, both autism and Rett syndrome belong to generalized developmental disorder (PDD), and many of their clinical manifestations are similar. The role of P2 gene mutation in autism has become a hot topic of research. In this study, five missense mutations (T197M, G232A, H371R, E394K, G428S) were found in 288 autistic patients and 384 normal controls. The functional studies showed that these five mutations did not affect the correct localization of MECP2 protein. The results of Real-Time PCR showed that T197M and G232A were severe transcriptional inhibition mutations, while the other three were not complete transcriptional inhibition mutations, which may be related to other functions. A deletion of copy number indicates that there is a certain correlation between the mutation of MECP2 gene and autism.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.61
本文编号：2238356
[Abstract]:Methyl-CpG binding protein 2 (MECP2) is a known transcription inhibitor with two characteristic functional domains: methylated DNA binding domain and transcription inhibitory domain. It plays an important role in neural development by regulating transcription, altering chromosomal conformation, and participating in RNA splicing. A large number of studies have shown that MECP2 gene mutations are associated with Rett syndrome, autism, mental retardation and other neurodevelopmental disorders, and have become a hot spot in the study of the relationship between the genotypes of disease susceptibility genes and various human neurodevelopmental diseases.
Drug addiction has become a prominent social and medical problem both at home and abroad. Long-term drug addiction is not only harmful to the physical and mental health of patients, but also susceptible to infection of AIDS, crime and so on. It is a serious social instability factor. Drug addiction is a chronic relapse characterized by loss of self-control and compulsive repeated use of drugs. Family studies have found that the heritability of drug dependence is as high as 54%. Attention to the role of genetic factors in drug dependence has gradually increased. In recent years, considerable progress has been made in the study of drug dependence, but the mechanism of dependence has not been fully elucidated. Fewer treatments play a role, but the overall effect is poor. Only by thoroughly understanding the biological mechanism of addiction can effective treatment and prevention be found. Some studies have shown that MECP2 gene and BDNF (Brain-derived neurotrophic factor) gene are susceptible genes for drug dependence, but most of the existing studies are physiological and morphological. In fact, the association between genetic polymorphism and drug dependence has not been reported.
In order to better understand the genetic mechanism of heroin addiction, the association between the polymorphisms of MECP2 and BDNF genes and heroin dependence was explored. The SNP loci of MECP2 and BDNF genes were sequenced and analyzed in 32 healthy controls, and the SNaPshot technique was used in 331 heroin addicts and 325 healthy controls. The results showed that the genotype and allele frequencies of MECP2 gene rs2075597, rs61751363 and rs189253298 were found in heroin dependent group and control group. The results showed that the rs189253298 polymorphism of MECP2 gene was associated with daily heroin use in heroin addicts, and the individuals with G allele used the sea every day. The allele frequencies of BDNF gene rs11030102 were significantly different between heroin addicts and controls (P 0.05). The genotype frequencies of rs11030101 and rs7124442 were significantly different between low dose group and high dose group (P = 0.033, P = 0.032). The rs11030101 and rs7124442 polymorphisms were associated with daily heroin use in heroin addicts. Individuals with T and G alleles had lower daily heroin use, which was a protective factor.
Autism, which usually begins in infancy, is a pervasive developmental disorder (PDD) characterized by language disorders, social disorders and stereotyped narrow interests. It is often associated with mental retardation, sensory and emotional abnormalities. It seriously affects the physical and mental development of children. Genetic factors play an important role in the pathogenesis of autism. Epidemiological studies in recent years have found that the number of autistic patients is increasing year by year. The etiology of autism may be related to X chromosome. In addition, both autism and Rett syndrome belong to generalized developmental disorder (PDD), and many of their clinical manifestations are similar. The role of P2 gene mutation in autism has become a hot topic of research. In this study, five missense mutations (T197M, G232A, H371R, E394K, G428S) were found in 288 autistic patients and 384 normal controls. The functional studies showed that these five mutations did not affect the correct localization of MECP2 protein. The results of Real-Time PCR showed that T197M and G232A were severe transcriptional inhibition mutations, while the other three were not complete transcriptional inhibition mutations, which may be related to other functions. A deletion of copy number indicates that there is a certain correlation between the mutation of MECP2 gene and autism.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.61
【参考文献】
相关期刊论文 前2条
1 孔静思;王亭芳;郑丽娜;左秋红;;孤独症的研究进展[J];生物学教学;2010年11期
2 刘可智;梁雪梅;郭兰婷;;儿童孤独症的遗传学研究进展[J];实用儿科临床杂志;2010年23期
，本文编号：2238356
本文链接：https://www.wllwen.com/yixuelunwen/jsb/2238356.html
最近更新
教材专著
