秦巴山區(qū)精神發(fā)育遲滯人群FMR1基因編碼區(qū)突變檢測(cè)研究
發(fā)布時(shí)間：2018-11-06 13:24
【摘要】：精神發(fā)育遲滯(Mental Retardation, MR)是一類神經(jīng)精神類疾病,嚴(yán)重危害兒童的身心健康,臨床表現(xiàn)為智力低下和社會(huì)適應(yīng)能力缺陷。脆性x綜合癥是一種常見(jiàn)的遺傳性MR,它是由于FMR1基因的異常導(dǎo)致的。與FMR1基因相關(guān)的MR的發(fā)病機(jī)制仍不十分清楚。大量研究發(fā)現(xiàn),患者FMR1基因5’-UTR區(qū)的(CGG) n的過(guò)度擴(kuò)增使得CpG島異常甲基化,最終導(dǎo)致基因沉默。還有報(bào)道認(rèn)為,即使FMR1基因的(CGG) n的擴(kuò)增數(shù)在正常范圍內(nèi),CpG島的異常甲基化也能導(dǎo)致MR發(fā)生。也有少數(shù)報(bào)道發(fā)現(xiàn),FMR1基因上的點(diǎn)突變也能引起MR。為了研究秦巴山區(qū)MR的遺傳病因,本課題組曾對(duì)秦巴山區(qū)MR人群的FMR1基因的(CGG) n重復(fù)數(shù)和CpG島的甲基化程度做了檢測(cè),發(fā)現(xiàn)了3例CpG島發(fā)生異常甲基化而(CGG) n重復(fù)數(shù)未見(jiàn)異常的MR患者。 為研究FMR1基因上的點(diǎn)突變與MR的關(guān)系,本論文采用PCR-SSCP技術(shù)并結(jié)合DNA測(cè)序,對(duì)秦巴山區(qū)410名MR患者的FMR1基因編碼區(qū)的17個(gè)外顯子進(jìn)行突變檢測(cè),結(jié)果在一名女性MR患者的DNA樣品中檢測(cè)到一個(gè)單堿基突變c.414GA。理論分析表明,此突變堿基是構(gòu)成FMR1基因編碼區(qū)第138個(gè)密碼子的第三個(gè)堿基,屬于同義突變,即p.Arg138Arg。為研究此突變是否影響mRNA的選擇性剪接,本論文采用RT-PCR技術(shù)結(jié)合克隆及測(cè)序技術(shù)分析了FMR1基因的cDNA序列,結(jié)果發(fā)現(xiàn)FMR1基因的12號(hào)外顯子發(fā)生了異常的選擇性剪接。突變患者體內(nèi)這種12號(hào)外顯子的異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.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.93
本文編號(hào)：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.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.93
【引證文獻(xiàn)】
相關(guān)碩士學(xué)位論文 前1條
1 程祿山;秦巴山區(qū)智力低下人群SRPX2基因編碼區(qū)突變檢測(cè)[D];西北大學(xué);2013年
，本文編號(hào)：2314404
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