本文選題：精神分裂癥 + DISC1�。� 參考：《濟(jì)南大學(xué)》2013年碩士論文

【摘要】：精神分裂癥（Schizophrenia，MIM181500）是一種以思維、情感、行為異常，精神活動(dòng)與環(huán)境不協(xié)調(diào)為特征的嚴(yán)重精神障礙，多發(fā)病于青壯年。在世界人口中的終生患病率為3.8‰-8.4‰；占全球范圍內(nèi)15～44歲人群疾病負(fù)擔(dān)的2.6%，是世界上導(dǎo)致殘疾的第四大原因。精神分裂癥的病因仍未查明，目前普遍認(rèn)為遺傳因素對(duì)其病因有重大影響，因?yàn)榫穹至寻Y的遺傳度約為80%，患者的一級(jí)親屬發(fā)病風(fēng)險(xiǎn)是普通人的5到10倍。精神分裂癥的遺傳機(jī)制十分復(fù)雜，一般認(rèn)為是由多對(duì)微效基因與環(huán)境因素共同作用所導(dǎo)致。通過(guò)遺傳連鎖和關(guān)聯(lián)分析，人們發(fā)現(xiàn)了很多與精神分裂癥病因有關(guān)的染色體區(qū)域和候選基因。 精神分裂癥斷裂基因（DISRUPTED IN SCHIZOPHRENIA， DISC1）位于1q42.2；全長(zhǎng)約410kb，包含13個(gè)外顯子，已發(fā)現(xiàn)有16個(gè)轉(zhuǎn)錄本。此基因編碼854個(gè)氨基酸的蛋白質(zhì)，包括一個(gè)富含絲氨酸、丙氨酸、甘氨酸的球狀N端區(qū)和一個(gè)由3-13號(hào)外顯子編碼形成的卷曲的C端區(qū)。羧基端區(qū)域富含許多環(huán)狀結(jié)構(gòu)域，有利于DISC1與其他蛋白間的結(jié)合。 鋅指蛋白804A（ZINC FINGER PROTEIN804A， ZNF804A）位于2q31，2008年，O’DONOVAN等人在全世界范圍內(nèi)首次發(fā)現(xiàn)了基于GWAS的精神分裂癥風(fēng)險(xiǎn)因子——遺傳標(biāo)記rs1344706，并鑒定出首選致病基因ZNF804A。隨后來(lái)自其他3個(gè)研究小組獨(dú)立的GWAS研究均證實(shí)了rs1344706與精神分裂癥的關(guān)聯(lián)，從而進(jìn)一步證明ZNF804A的研究?jī)r(jià)值。 目的 對(duì)精神分裂癥患者的DISC1基因和ZNF804A基因的全部外顯子進(jìn)行突變篩查，以求發(fā)現(xiàn)突變。 方法 階段一：DISC1基因外顯子突變篩查 選擇了2004年8月在山東省濟(jì)南市精神衛(wèi)生防治中心與濟(jì)南市歷城區(qū)錦繡川精神病療養(yǎng)院住院的精神分裂癥患者96例；正常對(duì)照者96例取自山東省血液中心獻(xiàn)血者。對(duì)DISC1基因的13個(gè)外顯子合成26對(duì)引物，，對(duì)96例精神分裂癥患者與96例正常對(duì)照者的DNA樣本分別進(jìn)行聚合酶鏈擴(kuò)增后，通過(guò)高分辨率熔解曲線（High Resolution Melting， HRM）方法對(duì)擴(kuò)增產(chǎn)物進(jìn)行突變檢測(cè)。 階段二：ZNF804A基因外顯子突變篩查 選擇了2004年8月在山東省濟(jì)南市精神衛(wèi)生防治中心與濟(jì)南市歷城區(qū)錦繡川精神病療養(yǎng)院住院的精神分裂癥患者182例；正常對(duì)照者96例取自山東省血液中心獻(xiàn)血者。對(duì)DISC1基因的4個(gè)外顯子合成20對(duì)引物，將182例精神分裂癥患者的DNA構(gòu)建2個(gè)DNA混合池，將96例正常對(duì)照者的DNA樣本構(gòu)建一個(gè)DNA混合池。首先將上述3個(gè)DNA混合池分別進(jìn)行聚合酶鏈擴(kuò)增，然后再將稀釋后的擴(kuò)增產(chǎn)物進(jìn)行COLD-PCR聚合酶鏈二次擴(kuò)增，最后用高分辨率熔解曲線（High Resolution Melting， HRM）方法對(duì)擴(kuò)增產(chǎn)物進(jìn)行突變檢測(cè)。 結(jié)果 1.用HRM方法對(duì)96例精神分裂癥患者和96例正常對(duì)照者的DISC1基因外顯子擴(kuò)增產(chǎn)物的熔解曲線分析未發(fā)現(xiàn)兩者的熔解曲線存在差別。 2.用HRM方法對(duì)182例精神分裂癥患者和96例正常對(duì)照者的ZNF804A基因外顯子擴(kuò)增產(chǎn)物熔解曲線分析在精神分裂癥患者Exon4.6位點(diǎn)發(fā)現(xiàn)多態(tài)性。 結(jié)論 本實(shí)驗(yàn)結(jié)果表明，在精神分裂癥患者DISC1基因外顯子的突變篩查沒(méi)有發(fā)現(xiàn)突變，在精神分裂癥患者ZNF804A基因Exon4.6位點(diǎn)發(fā)現(xiàn)多態(tài)性。DISC1基因可能與山東省精神分裂癥患者的發(fā)病無(wú)關(guān)，ZNF804A基因與山東精神分裂癥患者發(fā)病的關(guān)系仍待進(jìn)一步研究。
[Abstract]:Schizophrenia (MIM181500) is a serious mental disorder characterized by thought, emotion, abnormal behavior and incoordination between mental activity and environment. It is mostly in young adults. The lifetime prevalence rate in the world population is 3.8 per thousand -8.4 per thousand; it accounts for 2.6% of the disease burden of 15~44 years old in the world, which is the cause of disability in the world. Fourth major causes. The cause of schizophrenia is still not identified. It is widely believed that genetic factors have a significant impact on the cause of schizophrenia, because the heritability of schizophrenia is about 80%, the risk of first-degree relatives of the patients is 5 to 10 times that of ordinary people. The genetic mechanism of schizophrenia is very complex, generally thought to be from multiple pairs of genes and rings. Genetic linkage and association analysis have revealed many chromosomal regions and candidate genes related to the etiology of schizophrenia.
The schizophrenia gene (DISRUPTED IN SCHIZOPHRENIA, DISC1) is located in 1q42.2; a total of about 410KB, containing 13 exons and 16 transcripts. This gene encodes a 854 amino acid protein, including a spherical N endpoint rich in serine, alanine, glycine, and a curly C encoded by exon 3-13. The terminal region is rich in many ring domains, which is beneficial to the binding of DISC1 to other proteins.
The zinc finger protein 804A (ZINC FINGER PROTEIN804A, ZNF804A) was located in 2q312008, and O 'DONOVAN and others first discovered the risk factor of schizophrenia based on GWAS - genetic marker rs1344706, and identified the preferred pathogenic gene ZNF804A. subsequently from the independent GWAS studies of the other 3 research groups. 706 the association between schizophrenia and schizophrenia, thus further proving the value of ZNF804A research.
objective
Mutation screening of all exons of DISC1 gene and ZNF804A gene was performed in schizophrenic patients in order to detect mutations.
Method
Stage 1: DISC1 gene exon mutation screening
96 schizophrenic patients were selected in August 2004 in Ji'nan city of Shandong mental health prevention and control center and Ji'nan City District Jinxiu Sichuan spiritual sanatorium. 96 cases from the blood center of Shandong province were taken from the blood center of Shandong province. 13 exons of DISC1 gene were synthesized in 26 pairs, 96 schizophrenic patients and 96 cases were positive. The DNA samples of the normal controls were amplified by polymerase chain reaction, and the amplified products were detected by the high resolution fusion curve (High Resolution Melting, HRM).
Stage two: exon mutation screening for ZNF804A gene
182 schizophrenic patients were selected in August 2004 in Ji'nan city of Shandong mental health prevention and control center and Ji'nan City District Jinxiu Sichuan spiritual sanatorium. 96 cases from the blood center of Shandong province were taken from the blood center of Shandong province. 4 exons of DISC1 gene were synthesized in 20 pairs, and 182 schizophrenic patients were constructed. 2 DNA mixed pools were used to construct a DNA mixing pool in the DNA samples of 96 normal controls. First, the 3 DNA mixed pools were amplified by polymerase chain reaction, and then the amplified products were amplified by COLD-PCR polymerase chain for two times. Finally, the high resolution melting curve (High Resolution Melting, HRM) method was used to amplify the product. Mutation detection.
Result
1. the fusion curves of DISC1 exon amplification products of 96 schizophrenic patients and 96 normal controls were analyzed by HRM method, and there was no difference in the melting curve between the two.
2. HRM method was used to analyze the fusion curve of the exon amplification product of ZNF804A gene exon in 182 schizophrenic patients and 96 normal controls. The polymorphism was found in the Exon4.6 locus of schizophrenic patients.
conclusion
The results of this study showed that mutation screening was not found in the DISC1 exons of the schizophrenic patients. The polymorphism of the.DISC1 gene in the ZNF804A gene Exon4.6 locus in schizophrenic patients was not found to be related to the incidence of schizophrenia in Shandong, and the relationship between the ZNF804A gene and the incidence of Shandong schizophrenic patients was still to be entered. One step of research.

【學(xué)位授予單位】：濟(jì)南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.3

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