秦巴山区精神发育迟滞人群FMR1基因编码区突变检测研究
发布时间：2018-11-06 13:24
【摘要】：精神发育迟滞(Mental Retardation, MR)是一类神经精神类疾病,严重危害儿童的身心健康,临床表现为智力低下和社会适应能力缺陷。脆性x综合症是一种常见的遗传性MR,它是由于FMR1基因的异常导致的。与FMR1基因相关的MR的发病机制仍不十分清楚。大量研究发现,患者FMR1基因5’-UTR区的(CGG) n的过度扩增使得CpG岛异常甲基化,最终导致基因沉默。还有报道认为,即使FMR1基因的(CGG) n的扩增数在正常范围内,CpG岛的异常甲基化也能导致MR发生。也有少数报道发现,FMR1基因上的点突变也能引起MR。为了研究秦巴山区MR的遗传病因,本课题组曾对秦巴山区MR人群的FMR1基因的(CGG) n重复数和CpG岛的甲基化程度做了检测,发现了3例CpG岛发生异常甲基化而(CGG) n重复数未见异常的MR患者。 为研究FMR1基因上的点突变与MR的关系,本论文采用PCR-SSCP技术并结合DNA测序,对秦巴山区410名MR患者的FMR1基因编码区的17个外显子进行突变检测,结果在一名女性MR患者的DNA样品中检测到一个单碱基突变c.414GA。理论分析表明,此突变碱基是构成FMR1基因编码区第138个密码子的第三个碱基,属于同义突变,即p.Arg138Arg。为研究此突变是否影响mRNA的选择性剪接,本论文采用RT-PCR技术结合克隆及测序技术分析了FMR1基因的cDNA序列,结果发现FMR1基因的12号外显子发生了异常的选择性剪接。突变患者体内这种12号外显子的异常剪接可能正是其患有MR的主要原因。
[Abstract]:Mental retardation (Mental Retardation, MR) is a kind of neuropsychiatric disease, which seriously endangers the physical and mental health of children. Fragile x syndrome is a common hereditary MR, that is caused by abnormal FMR1 genes. The pathogenesis of MR associated with FMR1 gene is still unclear. A large number of studies have found that the overexpression of (CGG) n in the 5'-UTR region of the FMR1 gene in patients leads to abnormal methylation of the CpG island, which ultimately leads to gene silencing. It is also reported that aberrant methylation of the CpG island can lead to MR even if the (CGG) n amplification of the FMR1 gene is within a normal range. A few reports have found that point mutations in the FMR1 gene can also cause MR. In order to study the genetic cause of MR in Qinba Mountain area, our team tested the (CGG) n repeats of FMR1 gene and the methylation degree of CpG island in MR population in Qinba Mountain area. Three MR patients with abnormal methylation of CpG island and no abnormal (CGG) n repeats were found. In order to study the relationship between point mutation of FMR1 gene and MR, 17 exons of FMR1 gene coding region of 410 MR patients in Qinba Mountain region were detected by PCR-SSCP technique and DNA sequencing. Results A single base mutation c. 414 GA was detected in a DNA sample from a female MR patient. Theoretical analysis shows that this mutation is the third codon of the 138th codon in the coding region of FMR1 gene, which belongs to synonymous mutation, that is, p.Arg138Arg. In order to study whether this mutation affects the selective splicing of mRNA, the cDNA sequence of FMR1 gene was analyzed by RT-PCR technique combined with cloning and sequencing. It was found that abnormal selective splicing occurred in exon 12 of FMR1 gene. The abnormal splicing of exon 12 in mutant patients may be the main cause of MR.
【学位授予单位】：西北大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.93
本文编号：2314404
[Abstract]:Mental retardation (Mental Retardation, MR) is a kind of neuropsychiatric disease, which seriously endangers the physical and mental health of children. Fragile x syndrome is a common hereditary MR, that is caused by abnormal FMR1 genes. The pathogenesis of MR associated with FMR1 gene is still unclear. A large number of studies have found that the overexpression of (CGG) n in the 5'-UTR region of the FMR1 gene in patients leads to abnormal methylation of the CpG island, which ultimately leads to gene silencing. It is also reported that aberrant methylation of the CpG island can lead to MR even if the (CGG) n amplification of the FMR1 gene is within a normal range. A few reports have found that point mutations in the FMR1 gene can also cause MR. In order to study the genetic cause of MR in Qinba Mountain area, our team tested the (CGG) n repeats of FMR1 gene and the methylation degree of CpG island in MR population in Qinba Mountain area. Three MR patients with abnormal methylation of CpG island and no abnormal (CGG) n repeats were found. In order to study the relationship between point mutation of FMR1 gene and MR, 17 exons of FMR1 gene coding region of 410 MR patients in Qinba Mountain region were detected by PCR-SSCP technique and DNA sequencing. Results A single base mutation c. 414 GA was detected in a DNA sample from a female MR patient. Theoretical analysis shows that this mutation is the third codon of the 138th codon in the coding region of FMR1 gene, which belongs to synonymous mutation, that is, p.Arg138Arg. In order to study whether this mutation affects the selective splicing of mRNA, the cDNA sequence of FMR1 gene was analyzed by RT-PCR technique combined with cloning and sequencing. It was found that abnormal selective splicing occurred in exon 12 of FMR1 gene. The abnormal splicing of exon 12 in mutant patients may be the main cause of MR.
【学位授予单位】：西北大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.93
【引证文献】
相关硕士学位论文 前1条
1 程禄山;秦巴山区智力低下人群SRPX2基因编码区突变检测[D];西北大学;2013年
，本文编号：2314404
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