本文選題：常染色體顯性遺傳多囊腎疾病 + 顱內(nèi)動(dòng)脈瘤��； 參考：《鄭州大學(xué)》2017年碩士論文

【摘要】：背景和目的常染色體顯性遺傳多囊腎病(Autosomal Dominant Polycystic Kidney Disease,ADPKD)是一種醫(yī)學(xué)上較為容易遇到的、具有致命風(fēng)險(xiǎn)的常染色體單基因遺傳疾病。ADPKD患者通常是在中青年時(shí)確診,全世界大概有1/1000—1/400的人患有此病,1200多萬(wàn)人達(dá)到放射診斷標(biāo)準(zhǔn)而診斷為此病。相關(guān)研究表明,ADPKD通常由PKD1和PKD2兩種基因突變導(dǎo)致,PKD1位于16號(hào)常染色體短臂一區(qū)3帶3亞帶,PKD2位于4q21區(qū)。PKD1通過(guò)轉(zhuǎn)錄翻譯得到的產(chǎn)物為多囊蛋白1(polycystin-1,PC1),PKD2通過(guò)轉(zhuǎn)錄翻譯得到的產(chǎn)物多囊蛋白2(polycystin-2,PC2)。多囊蛋白1是一種血漿膜樣受體蛋白,主要分布在細(xì)胞膜上,維持細(xì)胞之間或是細(xì)胞與細(xì)胞外液之間的相互作用;多囊蛋白2是一種非選擇性的陽(yáng)離子通道,PC2與PC1結(jié)合后,形成復(fù)合物,該復(fù)合物對(duì)鈣離子有較強(qiáng)的通透性,對(duì)鈣離子起到門(mén)控通道的作用。位于6號(hào)染色體短臂一區(qū)2帶的PKHD1基因發(fā)生突變則會(huì)導(dǎo)致隱性遺傳多囊腎病的形成,PKHD1通過(guò)轉(zhuǎn)錄翻譯得到的產(chǎn)物FPC蛋白。對(duì)已發(fā)現(xiàn)的多囊腎病基因的致病位點(diǎn)的研究發(fā)現(xiàn),大片段缺失、重復(fù)或重排突變發(fā)現(xiàn)極少(約為3%—4%),ADPKD主要以點(diǎn)突變?yōu)橹鳌Ｒ虼?對(duì)患者的致病基因序列進(jìn)行直接測(cè)序仍然是對(duì)多囊腎病的基因診斷的主要技術(shù)。ADPKD是一種明確的基因座異質(zhì)性疾病,它的基因診斷相當(dāng)復(fù)雜,PKD1或PKD2兩個(gè)基因有一個(gè)出現(xiàn)致病突變即可引發(fā)ADPKD,其中多囊腎疾病多是由PKD1基因突變引起的,約為85%,臨床表型也最為嚴(yán)重,導(dǎo)致病人發(fā)展至終末期腎病的時(shí)間比PKD2要早20年。其次,從目前已有的研究來(lái)看,ADPKD基因突變并沒(méi)有像其它疾病一樣有固定的位點(diǎn),它的突變可能會(huì)發(fā)生在PKD1和PKD2基因的任何一個(gè)位點(diǎn),較難檢測(cè)。ADPKD的特點(diǎn)是雙腎多發(fā)囊腫和早發(fā)性慢性腎功能衰竭,最終將導(dǎo)致終末期腎病(ESRD),只能進(jìn)行腎替代治療或腎移植維持生命。除腎臟囊腫外,ADPKD通常還伴有肝囊腫、脾囊腫、胰囊腫、卵巢囊腫和精囊囊腫等腎外表現(xiàn),它也是顱內(nèi)動(dòng)脈瘤發(fā)生發(fā)展的重要危險(xiǎn)因素;多囊腎患者患動(dòng)脈瘤的概率為4%至41%。由于ADPKD有向家族聚集的傾向,而且該病一般發(fā)病較晚,多于成年引發(fā),十分不利于患者自身的治療,大多患者在結(jié)婚生子以后才被確診為多囊腎病,生出攜帶有致病突變的孩子概率很大,這對(duì)患者及其家屬和保健系統(tǒng)也造成了沉重的負(fù)擔(dān)。顱內(nèi)動(dòng)脈瘤(intracrartial aneurysm,IA)系顱內(nèi)動(dòng)脈血管壁發(fā)生病理性局限性擴(kuò)張形成的血管瘤樣病變,一般多會(huì)引發(fā)自發(fā)性蛛網(wǎng)膜下腔出血。顱內(nèi)動(dòng)脈瘤一旦發(fā)生破裂,具有極高的致死性和致殘性,而且目前并沒(méi)有具體的藥物來(lái)穩(wěn)定或預(yù)防其破裂,所以它是給患者生命和健康帶來(lái)很大威脅的一種疾病,也給家庭和社會(huì)也帶來(lái)了繁重的負(fù)擔(dān)。IA的發(fā)病機(jī)制尚未清楚,通常認(rèn)為它的發(fā)病是由多種因素共同引起的。目前研究已經(jīng)證實(shí)年齡、性別、抽煙、酗酒、高血壓、吸毒、季節(jié)、家族史是顱內(nèi)動(dòng)脈瘤的高危因素,也很可能是血流動(dòng)力改變化及后天退行性變等綜合作用的結(jié)果。然則相關(guān)研究報(bào)道,遺傳因素對(duì)于引發(fā)IA也起到了十分重要的作用。心血管并發(fā)癥是ADPKD的首要死因,而IA引起的蛛網(wǎng)膜下腔出血是其中最重要的并發(fā)癥。ADPKD中IA的診斷和治療策略還沒(méi)有被全面建立起來(lái)。IA是所有ADPKD患者心血管并發(fā)癥中最嚴(yán)重的一種,這是因?yàn)檠芰龅钠屏押箅S之而來(lái)的是50%的高死亡率。盡管多囊蛋白在動(dòng)脈平滑肌的表達(dá),這一PKD基因突變誘發(fā)動(dòng)脈瘤的形成機(jī)制仍然不完全清楚,PKD1和PKD2的突變對(duì)于IAs的發(fā)病風(fēng)險(xiǎn)相等�？拷黀KD1 5’端一半距離的位點(diǎn)的突變更容易發(fā)展成為IAs。數(shù)學(xué)建模表明,多流體填充腎間質(zhì)囊腫的形成起始于兒童期,從而導(dǎo)致早期顱內(nèi)動(dòng)脈瘤較難檢測(cè)。因此我們希望建立一個(gè)高效特異的檢測(cè)突變的體系,研究ADPKD伴發(fā)IA的患者PKD1突變與一般ADPKD患者突變的區(qū)別,找出基因?qū)用嫔陷o助診斷的方法,使ADPKD和IA在形成和潛伏期就可以被檢測(cè)出,以便及早治療,從而減免患者的痛苦。方法在上海交通大學(xué)附屬第六人民醫(yī)院收集并整理從2013年7月到2014年8月在該院接受治療的ADPKD患者,所有患者均經(jīng)B超、CT、磁共振血管成像法篩選伴有顱內(nèi)動(dòng)脈瘤的患者,共收集ADPKD伴發(fā)ICA患者23例。用乙二胺四乙酸(EDTA)抗凝管采取23例患者術(shù)前早晨空腹外周血4mL,置于冰箱中,試劑盒提取23例患者的基因組DNA。設(shè)計(jì)巢式PCR反應(yīng),分析所需的特異性引物,選擇六對(duì)長(zhǎng)片段引物,分別擴(kuò)增PKD1的1號(hào)外顯子、2到12號(hào)外顯子、13到15D號(hào)外顯子、外顯子15E到22、外顯子22到32、36到46號(hào)外顯子,選擇特異性好的PCR反應(yīng)條件進(jìn)行擴(kuò)增。把擴(kuò)增所得小片段產(chǎn)物進(jìn)行一代測(cè)序,對(duì)結(jié)果進(jìn)行分析。結(jié)果1所得PCR產(chǎn)物經(jīng)電泳驗(yàn)證,條帶高亮且產(chǎn)物唯一,特異性較好。2 23例樣本進(jìn)行測(cè)序后共檢出突變85個(gè)。這些突變均為點(diǎn)突變,其中47個(gè)錯(cuò)義突變,35個(gè)同義突變,1個(gè)無(wú)義突變,1個(gè)移碼突變。而且所有樣品均在7號(hào)外顯子檢測(cè)到同一突變。3共發(fā)現(xiàn)未知突變占19種,其中錯(cuò)義突變14種,同義突變3種,無(wú)義突變1種,移碼突變1種。結(jié)論1 PKD1 7號(hào)外顯子檢測(cè)到的同一突變,與普通PKD患者和正常人均不同,為多囊腎伴發(fā)動(dòng)脈瘤的研究提供了指引。2 PKD1靠近5'端一半距離共發(fā)現(xiàn)72個(gè)突變,占發(fā)現(xiàn)突變總數(shù)的84.70%,證明靠近PKD1 5'端一半距離的位點(diǎn)的突變更容易發(fā)展成為顱內(nèi)動(dòng)脈瘤。
[Abstract]:Background and objective autosomal dominant hereditary polycystic kidney disease (Autosomal Dominant Polycystic Kidney Disease, ADPKD) is a medicine that is relatively easy to meet. The fatal risk of autosomal monogenic genetic disease of.ADPKD patients is usually diagnosed in young and middle-aged people, and the world probably has 1/1000 1/400 people with this disease, more than 1200 The study showed that ADPKD was usually caused by two mutations of PKD1 and PKD2, PKD1 was located in the 3 band and 3 subband of the 16 autosomal short arm, and the product of PKD2 in 4q21 region.PKD1 through transcriptional translation was polycystic protein 1 (polycystin-1, PC1), and PKD2 was more than the product of transcriptional translation. The cysts 2 (polycystin-2, PC2). Polycystic protein 1 is a plasma membrane like receptor protein, mainly distributed on the cell membrane, maintaining the interaction between cells or between cells and extracellular fluid; polycystic protein 2 is a non selective cation channel, and the combination of PC2 and PC1 forms a complex, and the complex has a strong passage to calcium ions. PKHD1 gene mutation at the 2 band of the short arm of chromosome 6 will lead to the formation of recessive polycystic kidney disease and the product of PKHD1 through the transcriptional translation of FPC protein. Mutations found very little (about 3% to 4%) and ADPKD was mainly point mutation. Therefore, direct sequencing of the patient's gene sequence is still the main technique for genetic diagnosis of polycystic kidney disease (.ADPKD), a specific loci heterogeneity disease. Its genetic diagnosis is complex, and the two genes of PKD1 or PKD2 have one disease. Mutation can cause ADPKD, in which polycystic kidney disease is caused by a mutation of PKD1 gene, about 85%, and the most severe clinical phenotype, which causes the patient to develop to end-stage kidney disease 20 years earlier than PKD2. Secondly, from the present study, the mutation of the ADPKD gene does not have a fixed site like other diseases, and its mutation It may occur at any site of the PKD1 and PKD2 genes. It is difficult to detect.ADPKD, which is characterized by double renal multiple cysts and premature chronic renal failure, which will eventually lead to end-stage renal disease (ESRD), only renal replacement therapy or renal transplantation to maintain life. Except for renal cysts, ADPKD is usually accompanied by liver cysts, splenic cysts, and pancreatic cysts. Ovarian cysts and seminal vesicle cysts are also an important risk factor for the development of intracranial aneurysms. The incidence of aneurysms in patients with polycystic kidney disease is 4% to 41%. because ADPKD has a tendency to gather in the family, and the disease usually occurs later, more than the adult, and is very detrimental to the patient's own treatment, most of the patients are married. The child has been diagnosed with polycystic kidney disease after being diagnosed as polycystic kidney disease. It has a great probability to produce a child with a pathogenic mutation. It also causes a heavy burden on the patients and their families and health care systems. Intracranial aneurysms (intracrartial aneurysm, IA) are the angiomatoid lesions formed by the pathological localized dilatation of the vascular walls of the intracranial arteries. Onset of subarachnoid hemorrhage. Once intracranial aneurysm is ruptured, it is extremely lethal and disabled, and there is no specific drug to stabilize or prevent its rupture, so it is a disease that poses a great threat to the life and health of the patient, and also brings a heavy burden to the family and society with the pathogenesis of.IA. It is not clear that it is usually considered to be caused by a variety of factors. The current study has confirmed that age, sex, smoking, alcohol, hypertension, drug use, season, family history are the high risk factors for intracranial aneurysms, and may also be the results of the combined effects of changes in hemodynamic changes and acquired degeneration. Genetic factors also play an important role in the initiation of IA. Cardiovascular complications are the leading causes of ADPKD, and IA induced subarachnoid hemorrhage is the most important complication in.ADPKD. The diagnosis and treatment strategy of IA has not been fully established, and.IA is the most serious of all cardiovascular complications in ADPKD patients. It is because of the rupture of a hemangioma that follows a high death rate of 50%. Although polycystic protein is expressed in the arterial smooth muscle, the mechanism of the PKD gene mutation is still not completely clear, the mutation of PKD1 and PKD2 is equal to the risk of IAs. Mutations near the half distance of the PKD1 5 'end are more likely to occur. IAs. mathematical modeling shows that the formation of multifluid filling of renal interstitial cysts begins in childhood, which leads to early intracranial aneurysms which are difficult to detect. Therefore, we hope to establish an efficient and specific mutation detection system to identify the difference between the PKD1 mutation in the patients with IA and the mutation of a ADPKD patient, and to find out the gene level. The method of auxiliary diagnosis can be detected in the formation and incubation period of ADPKD and IA so as to treat early and reduce the sufferings of the patients. Methods at the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, the patients were collected and collected from July 2013 to August 2014. All patients were treated by B-ultrasound, CT, and magnetic resonance angiography. A total of 23 patients with intracranial aneurysms with intracranial aneurysms were selected, and 23 patients with ICA were collected. 23 patients with EDTA (EDTA) anticoagulant were placed in the fridge in the fridge. The genomic DNA. of 23 patients was extracted by the kit to design nested PCR reaction. The specific primers needed were analyzed, and six long segments were selected. We amplified PKD1 exon 1, exon 2 to 12, 13 to 15D exon, exon 15E to 22, exon 22 to 32,36 to exon 46, and selected specific PCR reaction conditions to amplify. The small fragment of the amplified fragment was sequenced and analyzed. The result 1 obtained the PCR product to be verified by electrophoresis. 23 samples were sequenced and 85 of the 23 samples were sequenced. All of these mutations were point mutations, including 47 missense mutations, 35 synonymous mutations, 1 unsense mutations and 1 code mutation. And all the samples were detected by the same sudden change.3 in 19 of the same sudden change, of which the missense mutation was 14. 3 kinds of synonymous mutagenesis, 1 non sense mutations and 1 kinds of shift mutation. Conclusion 1 PKD1 7 exons were detected by the same mutation, which were different from normal PKD patients and normal persons. The study provided a guide to the study of the polycystic kidney associated aneurysm by guiding the.2 PKD1 near the 5'end to find 72 sudden changes, accounting for 84.70% of the total number of mutations, which proved to be close to PKD1 5'. The mutation at the half distance is more likely to develop into intracranial aneurysms.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R692;R743

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