本文選題：發(fā)作性運(yùn)動(dòng)誘發(fā)性運(yùn)動(dòng)障礙 + 基因突變��； 參考：《天津醫(yī)科大學(xué)》2015年碩士論文

【摘要】：目的發(fā)作性運(yùn)動(dòng)誘發(fā)性運(yùn)動(dòng)障礙(paroxysmal kinesigenic dyskinesia,PKD)是一種罕見(jiàn)的、突然發(fā)作的運(yùn)動(dòng)障礙性疾病。目前認(rèn)為位于16號(hào)染色體上的富脯氨酸跨膜蛋白2(proline-rich transmembrane protein 2,PRRT2)基因可能是PKD的致病基因。因此,為了明確PRRT2基因突變與漢族人群PKD發(fā)生間的關(guān)系以及PRRT2基因突變與PKD患者臨床表型的關(guān)聯(lián),我們開(kāi)展了如下研究,旨在:1.了解PRRT2基因相關(guān)的生物學(xué)信息,包括基因結(jié)構(gòu)、編碼蛋白序列的結(jié)構(gòu)以及該基因編碼區(qū)單核苷酸多態(tài)性(single nucleotide polymorphisms,SNPs),為后續(xù)研究做準(zhǔn)備;2.明確漢族PKD患者PRRT2基因突變頻率以及PRRT2基因突變位點(diǎn)信息;3.探討PKD患者中PRRT2基因突變與臨床表型的關(guān)聯(lián)。方法1.通過(guò)生物網(wǎng)絡(luò)數(shù)據(jù)庫(kù)查找PRRT2基因,并進(jìn)行相關(guān)生物信息學(xué)分析,包括:查找該基因的基因組定位、結(jié)構(gòu)信息以及該基因編碼蛋白質(zhì)序列的跨膜結(jié)構(gòu)信息等。2.收集3個(gè)中國(guó)北方漢族PKD家系共12例患者及其26例無(wú)癥狀家屬、10例散發(fā)PKD患者和30例正常對(duì)照,由兩名神經(jīng)內(nèi)科醫(yī)生對(duì)納入本研究的所有患者進(jìn)行詳細(xì)檢查,然后記錄臨床資料,并抽取其外周血。3.對(duì)納入本研究的所有患者行PRRT2基因全外顯子測(cè)序,來(lái)明確PRRT2基因突變是否為北方漢族人群PKD的致病基因,隨后在正常對(duì)照中對(duì)相應(yīng)位點(diǎn)進(jìn)行驗(yàn)證。4.應(yīng)用SWISS-MODEL對(duì)PKD患者和正常對(duì)照PRRT2基因編碼的氨基酸序列進(jìn)行二級(jí)結(jié)構(gòu)的預(yù)測(cè)分析。5.對(duì)納入本研究的患者隨訪半年,觀察對(duì)給予卡馬西平等抗癲癇藥物治療的效果,并采用統(tǒng)計(jì)學(xué)的方法比較攜帶PRRT2基因突變的患者(陽(yáng)性組)和未攜帶PRRT2基因突變的患者(陰性組)臨床表型的差異。結(jié)果1.PRRT2基因定位于16p11.2,基因全長(zhǎng)3794bp,含有4個(gè)外顯子,m RNA全長(zhǎng)2606bp,CDS在m RNA的302~1324bp區(qū)域,編碼341個(gè)氨基酸。PRRT2蛋白存在兩個(gè)跨膜區(qū)域,分別在第269~289和318~338氨基酸之間。PRRT2基因編碼區(qū)共存在42個(gè)非同義SNPs和19個(gè)同義SNPs。2.全外顯子測(cè)序的結(jié)果發(fā)現(xiàn),在6例家族性PKD患者和3例散發(fā)PKD患者中發(fā)現(xiàn)PRRT2基因第2號(hào)外顯子發(fā)生雜合點(diǎn)突變412 CG(Pro138Ala),使編碼的脯氨酸(Proine)變成丙氨酸(Valine);在6例家族性PKD患者和2例散發(fā)PKD患者中發(fā)現(xiàn)PRRT2基因第3號(hào)外顯子發(fā)生雜合突變917 CA(Ala306Asp),使編碼的丙氨酸(Valine)變成天冬氨酸(Aspartic acid),但在所有正常對(duì)照者中均未發(fā)現(xiàn)這兩個(gè)基因突變位點(diǎn)。3.蛋白質(zhì)結(jié)構(gòu)預(yù)測(cè)分析結(jié)果顯示PRRT2基因發(fā)生917 CA(Ala306Asp)突變后,其蛋白質(zhì)二級(jí)結(jié)構(gòu)未發(fā)生變化,但由于PRRT2基因編碼的氨基酸序列相似度較低,未能給出412 CG(Pro138Ala)位點(diǎn)突變的預(yù)測(cè)結(jié)果。4.將納入本研究的22例PKD患者分為PRRT2基因突變陽(yáng)性組(發(fā)現(xiàn)突變)和基因突變陰性組(未發(fā)現(xiàn)突變),PRRT2基因突變陽(yáng)性組PKD患者較基因突變陰性組PKD患者發(fā)病年齡更早(平均發(fā)病年齡:10.31 vs 16.44,P=0.027);臨床癥狀是否對(duì)稱(chēng)和發(fā)病頻率在兩組中的差異具有統(tǒng)計(jì)學(xué)意義(P=0.007,P=0.027);在發(fā)作先兆方面,兩組患者差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.054)。經(jīng)過(guò)6個(gè)月隨訪后發(fā)現(xiàn):卡馬西平治療對(duì)攜帶PRRT2基因突變的患者全部有效(11/11,100%),但對(duì)未攜帶PRRT2基因突變的患者僅部分有效(4/9,44.4%)。5.通過(guò)家系內(nèi)比較,發(fā)現(xiàn)3個(gè)中國(guó)北方漢族PKD家系均有子代較父代發(fā)病年齡提前,病情加重的現(xiàn)象。結(jié)論1.在中國(guó)北方漢族人群中,PRRT2基因在家族性PKD患者中的突變頻率相對(duì)較高。PRRT2基因的2個(gè)錯(cuò)義突變?cè)诩{入本研究的患者中被檢測(cè)出來(lái),因此412 CG(Pro138Ala)和917 CA(Ala306Asp)這兩個(gè)錯(cuò)義突變可能是PKD的致病原因。2.攜帶PRRT2基因突變的患者較不攜帶PRRT2基因突變的患者發(fā)病年齡更早,發(fā)作時(shí)的癥狀更為對(duì)稱(chēng),發(fā)作更為頻繁。同時(shí)研究顯示攜帶PRRT2基因突變的患者對(duì)卡馬西平等抗癲癇藥物治療的反應(yīng)性更好,因此PRRT2基因檢測(cè)可能對(duì)PKD患者的臨床治療具有潛在的指導(dǎo)意義。3.中國(guó)北方漢族PKD家系中可能存在遺傳早現(xiàn)現(xiàn)象。
[Abstract]:Objective paroxysmal kinesigenic dyskinesia (PKD) is a rare, sudden onset of dyskinesia. It is now considered that the proline rich transmembrane protein 2 (proline-rich transmembrane protein 2, PRRT2) gene located on chromosome 16 may be a pathogenic gene of PKD. Therefore, in order to clear PR The relationship between RT2 gene mutation and the occurrence of PKD in the Han population, and the association of PRRT2 gene mutations with the clinical phenotype of PKD patients. We have conducted the following studies: 1. to understand the biological information related to the PRRT2 gene, including the structure of the gene, the structure of the encoded protein sequence and the single nucleotide Po (single nucleotide PO). Lymorphisms, SNPs), prepare for the follow-up study; 2. clarify the frequency of PRRT2 mutation and the mutation site information of PRRT2 gene in the PKD patients of Han nationality; 3. explore the association between the mutation of the PRRT2 gene and the clinical phenotype in the PKD patients. Method 1. find the PRRT2 gene by the biological network database and carry out the related bioinformatics analysis, including the search of the gene. The genomic location, structural information and the transmembrane structure information of the gene encoding protein sequence were collected from 3 Chinese northern Han PKD families and 26 cases of asymptomatic families, 10 cases of PKD patients and 30 normal controls. Two neurosurgeon examined all the patients in this study, and then examined all the patients in this study. The clinical data were recorded and the peripheral blood.3. was extracted from all the patients in the study. The PRRT2 gene exon sequencing was performed to determine whether the PRRT2 gene mutation was the pathogenic gene of PKD in the northern Han population. Subsequently, the corresponding loci were verified in normal controls by the.4. application of SWISS-MODEL to the PKD patients and the normal control PRRT2 genes. The predictive analysis of the amino acid sequence of the two stage structure.5. was followed up for six months in the patients who were included in the study. The results were observed for the treatment of C Masi Bing and other antiepileptic drugs. Statistical methods were used to compare the differences in the clinical phenotype of patients (positive group) with PRRT2 gene mutation (positive group) and those who did not carry the PRRT2 gene mutation (negative group). Results the 1.PRRT2 gene was located in 16p11.2, with a full length of 3794bp, 4 exons, m RNA full length 2606bp, CDS in 302~1324bp region of M RNA, and two transmembrane regions encoding 341 amino acid.PRRT2 proteins. There were 42 unsynonymous and 19 synonyms in the gene coding region between the first 269~289 and the amino acids. Exon sequencing results found that the heterozygous mutation 412 CG (Pro138Ala) of the PRRT2 gene exon second was found in 6 familial PKD patients and 3 patients with PKD, and the encoded proline (Proine) was transformed into alanine (Valine), and the heterozygous exons of the PRRT2 gene were found in 6 familial PKD patients and 2 sporadic PKD patients. The mutation of 917 CA (Ala306Asp) changed the encoded alanine (Valine) into aspartic acid (Aspartic acid), but none of the two gene mutations found in all the normal controls showed that the protein structure of the PRRT2 gene was 917 CA (Ala306Asp) mutation, and the protein two structure did not change, but it was due to PRRT2. The gene encoded amino acid sequence was less similar and failed to predict the mutation of 412 CG (Pro138Ala) site..4. would be included in 22 PKD patients in this study into PRRT2 gene mutation positive group (discovery mutation) and gene mutation negative group (no mutation), and PRRT2 gene mutation positive group PKD patients were compared with PKD patients with gene mutation negative group. The age of the disease was earlier (average age of onset: 10.31 vs 16.44, P=0.027); the differences in the symmetry and frequency of clinical symptoms in the two groups were statistically significant (P=0.007, P=0.027); there was no statistical difference between the two groups (P=0.054) in the onset omen (P=0.054). After 6 months of follow-up, it was found that the C Masi Bing therapy had a mutation of the PRRT2 gene. The patients were all effective (11/11100%), but only partially effective (4/9,44.4%).5. of the patients who did not carry the PRRT2 gene mutation (4/9,44.4%) through family comparison, it was found that all of the PKD families of the Han nationality in the north of China had the earlier age of the parent generation and the aggravation of the disease. Conclusion 1. in the Han population of northern China, the PRRT2 gene is in the familial PKD patients. The 2 missense mutations of a relatively high mutation frequency of the.PRRT2 gene were detected in the patients enrolled in this study, so 412 CG (Pro138Ala) and 917 CA (Ala306Asp), two missense mutations, may be the cause of PKD in the pathogenesis of.2. with the PRRT2 gene mutation in the patients who are not carrying the PRRT2 gene mutation earlier, at the time of the onset of the attack. The symptoms are more symmetrical and more frequent. At the same time, the study shows that patients with PRRT2 gene mutations have better reactivity to C Masi Bing and other antiepileptic drugs, so PRRT2 gene detection may have a potential guiding significance for the clinical treatment of PKD patients.3. may exist in the PKD family of the Han nationality in Northern China.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R741

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本文編號(hào)：1775945