本文選題：視網(wǎng)膜色素變性 + PRPF31�。� 參考：《鄭州大學》2017年碩士論文

【摘要】：研究背景和目的視網(wǎng)膜色素變性(Rentinitis pigmentosa,RP,OMIM:268000)是光感受器細胞(包括視桿細胞和視錐細胞)異常而導致的遺傳性視網(wǎng)膜疾病。RP在世界范圍內的發(fā)病率約為1/5000-1/3500;在我國,RP的發(fā)病率也在逐年上升,約為l/l000,是引起失明的重要原因之一。根據(jù)是否同時伴隨其他眼部癥狀,RP可以分為綜合征型視網(wǎng)膜色素變性(Syndromic retinitis pigmentosa)和非綜合征型視網(wǎng)膜色素變性(Nonsyndromic retinitis pigmentosa,NSRP),其中NSRP約占RP的65%。RP的發(fā)病機制異常復雜,涉及多種不同的生物代謝途徑。其致病基因所編碼的蛋白主要參與光傳導、感光細胞結構的維持以及m RNA剪接等過程。不同生物途徑中各種蛋白的編碼基因突變而使蛋白功能受損,都可能導致光感受器細胞的異常,引起RP的發(fā)生。2012年,許菲等在一個常染色體顯性遺傳RP家系的研究中發(fā)現(xiàn)PRPF31基因的7號外顯子上有一個c.544_618del75bp的新發(fā)突變。但是,許菲等的研究選取的家系并不完整,只是該家族大家系中的一小部分;另外由于RP具有極強的臨床和遺傳異質性,可能存在新的尚未發(fā)現(xiàn)的致病突變位點;并且許菲等的研究沒有對該c.544_618del75bp缺失突變具體機制和功能進行深入探索。因此,我們對該家系進行補充和完善,對許菲的研究結果在整個大家系中進行驗證,同時尋找新的致病突變,進一步闡明基因型和表型的關系,并對c.544_618del75bp缺失突變的功能進行初步研究,為RP的分子遺傳機制及臨床診斷和治療提供理論依據(jù)。研究對象對許菲等研究的RP家系進行補充和完善,并對該家系成員進行了詳細的病史采集和眼科檢查,對家系內患者進行了確診。詳細了解該家系成員的信息后繪制家系系譜。抽取該家系成員外周靜脈血5mL。此外,隨機選取100名健康個體作為正常對照,抽取外周血5mL。本研究通過了鄭州大學倫理委員會的審批,所有受試者均知情同意。研究方法1.本研究采用全血基因組提取試劑盒提取了外周血基因組DNA,對該RP家系成員提取了RNA,并反轉錄成cDNA。2.對該家系中全部成員和100名健康對照通過sanger測序進行PRPF31基因c.544_618del75bp突變位點的測序篩查驗證,鑒定該基因型與表型在家系中的共分離。并且對家系內患者的基因組cDNA進行c.544_618del75bp突變位點的sanger測序驗證。3.對該突變位點進行生物信息學功能分析,并通過SWISS MODEL軟件預測野生型和突變型PRPF31基因編碼蛋白的三維結構。4.采用實時熒光定量RT-PCR技術檢測該家系中患者和正常人的外周血中PRPF31基因mRNA的表達水平。構建攜帶野生型和突變型PRPF31基因的過表達載體并采用質粒提取試劑盒進行提取和純化,其后轉染293T細胞,通過Western blot檢測野生型和突變型基因編碼蛋白在293T細胞內是否有表達。運用RT-PCR技術在轉染野生型和突變型過表達載體的293T細胞中檢測PRPF31基因mRNA的表達水平,驗證突變對PRPF31基因功能的影響。5.通過查閱文獻及The Human Protein Atlas數(shù)據(jù)庫篩選和mRNA剪切相關并且在人類外周血中有表達的RP9、ROM1、SNRNP200和TOPORS等基因。運用實時熒光定量RT-PCR技術在該家系患者和正常人的外周血中檢測這些基因mRNA的表達水平,并在轉染野生型和突變型過表達載體的293T細胞中驗證這些基因的表達情況。6.采用SPSS21.0統(tǒng)計軟件進行數(shù)據(jù)分析。家系內患者與健康對照之間mRNA的表達水平采用獨立樣本t檢驗進行統(tǒng)計分析,所有定量資料用均數(shù)±標準差(mean±SD)表示,運用Bivariate相關性分析,對家系內所有成員中PRPF31基因的mRNA表達水平與其相關基因的mRNA表達水平分別進行相關性分析。P0.05具有統(tǒng)計學意義。結果1.該家系內大部分患者都在10歲前發(fā)病,均以夜盲為首發(fā)癥狀,伴有視力有下降、視野缺損等癥狀,眼底檢查表明視盤顏色相對正常,但有不同程度的視網(wǎng)膜色素細胞萎縮。2.經(jīng)過sanger測序發(fā)現(xiàn)所有患者的DNA和cDNA中都攜帶有PRPF31基因c.544_618del75bp突變。除1例外顯不全成員外,家系內正常人和100例健康對照中則沒有檢測到該突變。本研究結果與許菲等人的研究結果一致。此外,我們在PRPF31基因上發(fā)現(xiàn)了一個IVS6-78_IVS6-75del4CACA的缺失突變,但所有患者中均未發(fā)現(xiàn)該突變。這兩個缺失突變同時存在于家系中的1例外顯不全的成員中,并且位于不同的染色體上。家系內正常人中IVS6-78_IVS6-75del4CACA缺失突變發(fā)生率為31.4%,且都為雜合突變。100例健康對照有38%的人有IVS6-78_IVS6-75del4CACA突變并且均為雜合突變,其等位基因的頻率為21.5%。3.利用SWISS MODEL對c.544_618del75bp突變型PRPF31基因所編碼的蛋白進行三維結構的預測,結果提示蛋白的結構發(fā)生了比較明顯的缺失改變。利用Mutation Taster在線軟件對PRPF31基因上的c.544_618del75bp突變位點和IVS6-78_IVS6-75del4CACA突變位點進行功能預測,結果顯示c.544_618del75bp缺失是一種致病突變,能夠造成氨基酸序列的改變和剪切位點的改變,進而可能造成蛋白質結構的改變。而IVS6-78_IVS6-75del4CACA位點能夠使剪切位點發(fā)生改變,可能改變蛋白質的結構。4.通過實時熒光定量RT-PCR技術在家系內16例患者與26例正常對照之間對PRPF31基因mRNA表達水平進行比較,發(fā)現(xiàn)患者外周血中PRPF31基因的mRNA表達水平(0.65±0.40)顯著低于正常對照(1.35±1.15),差異有統(tǒng)計學意義(P0.05)。構建攜帶野生型和突變型PRPF31基因的過表達載體并轉染293T細胞后,Western blot檢測到突變型和野生型PRPF31的過表達載體在293T細胞內能夠正常表達,采用實時熒光定量RT-PCR檢測PRPF31基因的mRNA表達水平,發(fā)現(xiàn)野生型和突變型PRPF31基因轉染組PRPF31基因mRNA表達水平顯著高于陰性對照組(P0.001),且野生型PRPF31基因的mRNA表達水平顯著高于突變型(P0.001)。5.采用實時熒光定量RT-PCR在家系內16例患者與26例正常對照之間檢測RP9、ROM1、SNRNP200和TOPORS等基因的mRNA的表達水平,發(fā)現(xiàn)患者外周血中RP9和ROM1基因mRNA的表達水平(分別是0.52±0.34和0.79±0.67)顯著低于正常對照(分別是1.50±1.13和1.74±1.72),差異有統(tǒng)計學意義(P0.05)。運用Bivariate相關性分析,對家系內39例成員(16例患者與26例正常對照者)的PRPF31基因的mRNA表達水平與RP9、ROM1基因的mRNA表達水平分別進行相關性分析,結果顯示:PRPF31基因與RP9基因的mRNA表達水平呈顯著的正相關(r=0.71,P=0.000)。在轉染后的293T細胞中對RP9、ROM1、SNRNP200和TOPORS基因的表達水平進行體外驗證,發(fā)現(xiàn)突變型PRPF31轉染組中RP9的表達水平低于野生型轉染組,但是差異沒有統(tǒng)計學意義。結論1.PRPF31基因的雜合突變c.544_618del75bp可能是該視網(wǎng)膜色素變性家系的致病突變,而IVS6-78_IVS6-75del4CACA缺失突變可能是一個多態(tài)位點。2.PRPF31基因c.544_618del75bp致病突變能夠降低該基因的mRNA表達水平,這可能是PRPF31基因c.544_618del75bp突變導致RP發(fā)生的重要機制。3.PRPF31基因c.544_618del75bp突變能夠使ADRP相關基因RP9的表達水平顯著降低,表明PRPF31基因的c.544_618del75bp突變可能通過影響RP9的正常功能導致RP的發(fā)生。
[Abstract]:Background and objective retinal pigment degeneration (Rentinitis pigmentosa, RP, OMIM:268000) is an abnormal genetic retinal disease caused by the abnormalities of photoreceptor cells (including rod cells and cone cells) and the incidence of.RP in the world is about 1/5000-1/3500; in China, the incidence of RP is also rising year by year, about l/l000, which is a cause of loss. One of the important reasons of Ming is that RP can be divided into Syndromic retinitis pigmentosa (retinitis pigmentosa) and non syndrome type retinal pigment degeneration (Nonsyndromic retinitis pigmentosa, NSRP) according to whether it is accompanied by other ocular symptoms at the same time. The same biological metabolic pathway. The protein encoded by its pathogenic gene mainly participates in the process of light conduction, the maintenance of photosensitive cell structure and the splicing of M RNA. The mutation of the encoding genes of various proteins in different biological pathways may cause the damage of the protein function, which may cause the abnormal of the photoreceptor cells, cause the occurrence of RP in.2012 years, and so on. In the study of an autosomal dominant hereditary RP family, a new mutation of c.544_618del75bp was found in exon 7 of the PRPF31 gene. However, the studies selected by xanphi were not complete, only a small part of the family family. In addition, because of the strong clinical and genetic heterogeneity of RP, there may be new yet new ones. The findings of the found mutation site, and the study of Xu Fei, did not explore the specific mechanism and function of the c.544_618del75bp deletion mutation. Therefore, we supplemented and perfected the family. The results of the study were verified in the whole family, and a new pathogenic mutation was found, and the genotypes and tables were further clarified. The function of c.544_618del75bp deletion mutation was preliminarily studied in order to provide a theoretical basis for the molecular genetic mechanism and clinical diagnosis and treatment of RP. The research subjects supplemented and perfected the RP families of the study of Xu Fei, and carried out a detailed history collection and ophthalmology examination for the family members of the family. The family members of the family were given a detailed understanding of the family genealogy. In addition to the peripheral venous blood 5mL. of the family members, 100 healthy individuals were selected as normal controls, and the 5mL. of the peripheral blood was selected for examination and approval of the Zhengzhou University ethics committee. All the subjects were informed consent. The study method was adopted in 1. studies. The whole blood genome Extraction Kit extracted genomic DNA from peripheral blood, extracted RNA from the members of the RP family, and reverse transcriptional cDNA.2. to all members of the family and 100 healthy controls by sequencing the c.544_618del75bp mutation site of the PRPF31 gene by Sanger sequencing to identify the genotype and phenotype in the family. And the Sanger sequencing of the c.544_618del75bp mutation site of the genome cDNA in the family of families verifies that.3. has a bioinformatics function analysis on the mutation site, and the SWISS MODEL software is used to predict the three dimensional structure of the wild and mutant PRPF31 gene encoding proteins by the real-time fluorescent quantitative RT-PCR technology for the detection of the family. The expression level of PRPF31 gene mRNA in the peripheral blood of the patients and normal people. The overexpression vector carrying the wild type and the mutant PRPF31 gene was constructed and the Plasmid Extraction Kit was used to extract and purify it. Then the 293T cells were transfected, and the Western blot was used to detect whether the wild type and mutant gene encoded proteins were in 293T cells. The expression level of PRPF31 gene mRNA was detected by RT-PCR technique in 293T cells transfected with wild type and mutant overexpressed vector, and the effect of mutation on the function of PRPF31 gene was verified by screening the literature and The Human Protein Atlas database screening and mRNA shear correlation and expressed in human peripheral blood. P200 and TOPORS genes. The expression of these genes was detected in the peripheral blood of the family and normal people by real time fluorescence quantitative RT-PCR, and the expression of these genes was verified in the 293T cells transfected with wild type and mutant overexpressed vector..6. was used for data analysis by SPSS21.0 statistics software. The expression level of mRNA was statistically analyzed by independent sample t test, and all quantitative data were expressed with mean mean + standard deviation (mean + SD), and Bivariate correlation analysis was used to analyze the mRNA expression level of PRPF31 gene in all members of the family and the mRNA expression level of related genes respectively. 05 the results were statistically significant. 1. most of the patients in the family were onset before the age of 10, with night blindness as the first symptom, accompanied by visual loss, visual field defect and other symptoms. Fundus examination showed that the color of the optic disc was relatively normal, but a different degree of retinal pigment cell atrophy.2. was found in all patients' DNA and cDNA through Sanger sequencing. The PRPF31 gene c.544_618del75bp mutation was carried. The mutation was not detected in normal people in the family and in 100 healthy controls except for 1 exceptions. The results of this study were in accordance with the results of Xu Fei et al. In addition, we found a IVS6-78_IVS6-75del4CACA deletion mutation in the PRPF31 gene, but all the patients were found to have a deletion mutation. The two deletion mutations were found in 1 exceptions in the family and on different chromosomes. The incidence of IVS6-78_IVS6-75del4CACA deletion mutations in normal families was 31.4%, and all of the.100 cases with heterozygous mutations had a IVS6-78_IVS6-75del4CACA mutation in 38% of the healthy controls. A heterozygous mutation, the frequency of its allele is 21.5%.3. using SWISS MODEL to predict the three-dimensional structure of the protein encoded by the c.544_618del75bp mutant PRPF31 gene. The results suggest that the structure of the protein has a distinct deletion change. Mutation Taster online software is used for the c.544_618del75bp process on PRPF31 gene. The functional prediction of variable sites and IVS6-78_IVS6-75del4CACA mutation sites shows that c.544_618del75bp deletion is a kind of pathogenic mutation, which can cause changes in the amino acid sequence and the shear site, and may cause the change of protein structure. The IVS6-78_IVS6-75del4CACA site can change the shear site and may be possible to change the shear site. The structure of protein.4. was compared with the mRNA expression level of the PRPF31 gene between 16 patients in the family and 26 normal controls by real-time fluorescence quantitative RT-PCR. It was found that the mRNA expression level of the PRPF31 gene in the peripheral blood of the patients was significantly lower than that of the normal control (1.35 + 1.15), and the difference was statistically significant (P0.05). After carrying the overexpressed vector of the wild type and mutant PRPF31 gene and transfecting 293T cells, Western blot detected that the overexpressed vector of mutant and wild type PRPF31 could be expressed normally in 293T cells. The mRNA expression level of PRPF31 gene was detected by real-time quantitative RT-PCR, and PR and mutant PRPF31 gene transfection group PR was found. The expression level of mRNA in the PF31 gene was significantly higher than that in the negative control group (P0.001), and the mRNA expression level of the wild type PRPF31 gene was significantly higher than that of the mutant type (P0.001).5. using real-time fluorescent quantitative RT-PCR in 16 patients in the family and 26 normal controls to detect the expression level of RP9, ROM1, SNRNP200, and TOPORS. The expression level of RP9 and ROM1 gene mRNA in blood (0.52 + 0.34 and 0.79 + 0.67 respectively) was significantly lower than that of normal controls (1.50 + 1.13 and 1.74 + 1.72 respectively). The difference was statistically significant (P0.05). The mRNA expression level of the PRPF31 gene in 39 members of the family (16 patients and 26 normal controls) by Bivariate correlation analysis and RP9, RO The correlation analysis of the mRNA expression level of the M1 gene showed that the mRNA expression level of the PRPF31 gene was positively correlated with the mRNA expression level of the RP9 gene (r=0.71, P=0.000). The expression level of RP9, ROM1, SNRNP200 and TOPORS genes in the transfected 293T cells was verified in vitro, and the expression level of the mutant transfection group was found. It is lower than the wild type transfection group, but the difference is not statistically significant. Conclusion the heterozygous mutation c.544_618del75bp of the 1.PRPF31 gene may be a pathogenic mutation of the retina pigmented family, and the IVS6-78_IVS6-75del4CACA deletion mutation may be a polymorphic locus of the.2.PRPF31 gene c.544_618del75bp pathogenic mutation to reduce the mR of the gene. The expression level of NA, which may be an important mechanism of the mutation of the PRPF31 gene c.544_618del75bp, causes the.3.PRPF31 gene c.544_618del75bp mutation to significantly reduce the expression level of the ADRP related gene RP9, indicating that the c.544_618del75bp mutation of the PRPF31 gene may lead to the occurrence of RP by affecting the normal function of RP9.

【學位授予單位】：鄭州大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R774.13

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