本文選題：原發(fā)性 + 肌張力障礙　； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年博士論文

【摘要】：背景 肌張力障礙(dystonia)(包括扭轉(zhuǎn)痙攣、眼瞼痙攣、口下頜肌張力障礙、痙攣性斜頸、痙攣性構(gòu)音障礙、書寫痙攣等)是一類病理生理復(fù)雜、機(jī)制未明的運(yùn)動障礙病。臨床癥狀以肌肉不自主收縮為特征,常導(dǎo)致扭轉(zhuǎn)、重復(fù)性運(yùn)動或異常姿勢,部分患者僅表現(xiàn)為震顫。迄今為止,全世界共發(fā)現(xiàn)20余種基因與原發(fā)性肌張力障礙有關(guān),其中DYT25/GNAL基因于2012年新近發(fā)現(xiàn),國內(nèi)外對其研究處于初步階段,國內(nèi)尚缺乏大規(guī)模人群研究。 目的 本研究旨在一個大樣本的中國原發(fā)性肌張力障礙患者中進(jìn)行GNAL基因突變篩查,明確我國肌張力障礙人群GNAL基因突變頻率及常見突變位點(diǎn)。方法 納入就診于北京協(xié)和醫(yī)院神經(jīng)內(nèi)科運(yùn)動障礙病門診的原發(fā)性肌張力障礙患者214例(陽性家族史患者12例),同時募集100例健康者作為對照組,留取外周血提取基因組DNA。對GNAL基因全部12個外顯子和5'UTR區(qū)進(jìn)行PCR擴(kuò)增,產(chǎn)物直接測序。測序發(fā)現(xiàn)的變異在對照組中用同樣方法進(jìn)行篩查,并運(yùn)用生物信息學(xué)軟件分析預(yù)測變異對蛋白的影響。同時檢索國內(nèi)外GNAL基因突變篩查研究,計算各研究中GNAL基因的突變頻率,并與本研究結(jié)果進(jìn)行對比。 結(jié)果 本研究對214例原發(fā)性肌張力障礙患者進(jìn)行GNAL基因突變篩查,結(jié)果發(fā)現(xiàn)11個變異位點(diǎn),分別是：c.-37AG, c.-41TC, c.-111CT, c.-116AG, c.-142GC, c.-485TC, c.15CT (p.G5=), c.30GT (p.T10=), c.44GA (p.G15D), c.1059CT (p.A353=), c.360CT (p.S120=)。正常對照組未發(fā)現(xiàn)以上變異。其中c.360CT(p.S120=), c-111CT, c.-41TC, c.-37AG, c.30GT (p.T10=)和c.44GA(p.G15D)為已知SNP位點(diǎn),編號分別為rs76888098, rs61495657, rs9303742, rs200432196, rs78167172和-199761315,認(rèn)為以上6個變異位點(diǎn)為良性變異,非致病突變。c.15CT(p.G5=),c.30GT(1).T10=),c.1059CT(p.A353=)和c.360CT(p.S120=)屬同義突變,編碼氨基酸未發(fā)生變化,認(rèn)為是非致病突變。應(yīng)用Mutation Taster對c.-485TC, c.-142GC, c.-116AG進(jìn)行預(yù)測,結(jié)果顯示為多態(tài)性改變�？傮w而言,本研究未發(fā)現(xiàn)明確致病突變。對國內(nèi)外文獻(xiàn)進(jìn)行回顧,不同種族人群中原發(fā)性肌張力障礙患者GNAL基因突變頻率差異很大,在0%-15.38%不等。 結(jié)論 本研究對中國214例原發(fā)性肌張力障礙患者進(jìn)行GNAL基因突變篩查,結(jié)果未發(fā)現(xiàn)明確致病突變,認(rèn)為GNAL基因突變非中國人群原發(fā)性肌張力障礙的常見致病基因。 背景 痙攣性斜頸(cervical dystonia,CD)是臨床上最常見的局灶型肌張力障礙,以頸部肌肉不自主收縮導(dǎo)致頭頸部運(yùn)動和姿勢異常為特征。病因尚不明確,遺傳因素可能參與其中。最近研究發(fā)現(xiàn),DYT23/CIZ1、DYT24/AN03和DYT25/GNAL基因突變可能與原發(fā)性肌張力障礙,特別是顱頸段肌張力障礙相關(guān)。目前國內(nèi)外關(guān)于以上3個基因的研究較少,國內(nèi)尚無原發(fā)性痙攣性斜頸家系的遺傳學(xué)研究。 目的 本研究旨在對中國漢族人群原發(fā)性痙攣性斜頸家系進(jìn)行CIZ1、AN03和GNAL基因突變篩查,明確我國家族性原發(fā)性痙攣性斜頸患者的常見突變基因及其突變頻率。 方法 納入就診于北京協(xié)和醫(yī)院神經(jīng)內(nèi)科運(yùn)動障礙病門診的中國漢族原發(fā)性痙攣性斜頸家系20個,同時募集100名健康受試者作為對照組,留取外周血提取基因組DNA。對先證者的CIZ1、AN03.GNAL基因全部外顯子和GNAL基因5'UTR區(qū)進(jìn)行PCR擴(kuò)增,產(chǎn)物直接測序。測序發(fā)現(xiàn)的變異在對照組中用同樣方法進(jìn)行篩查,并運(yùn)用生物信息學(xué)軟件分析預(yù)測變異對蛋白的影響。計算我國原發(fā)性痙攣性斜頸家系各基因的突變頻率,并與既往研究結(jié)果進(jìn)行對比。 結(jié)果 本研究對中國漢族20個原發(fā)性痙攣性斜頸家系進(jìn)行CIZl、AN03和GNAL基因突變篩查,結(jié)果：在CIZ1基因發(fā)現(xiàn)兩個同義突變,分別為c.696GA(p.P232＝)和c.1227CA(p.P409=),編碼氨基酸未發(fā)生變化,SNP編號為rs45579839和rs45559035,考慮非致病突變；在AN03基因發(fā)現(xiàn)7個變異位點(diǎn),分別為c.-11GT,c.1158AG(p.L386=),c.1692AC(p.A564=),c.2682CT(p.P894=),c.2478CG,(p.T826=),c.2520TG(p.R840=)和c.2540AG(p.Y847C),健康對照組檢測到c.1158AG(p.L386=),c.1692AC(p.A564=)和c.2682CT(p.P894=)。其中c.-11GT,c.1158AG(p.L386=),c.1692AC(p.A564=)和c.2682CT(p.P894=)為已知SNP位點(diǎn),編號分別為rS143269109,rs2663168,rs11604768和rs10835051.c.2478CG(p.T826=)和c.2520TG(p.R840=)為同義突變,編碼氨基酸未發(fā)生變化,認(rèn)為以上6個變異為非致病突變。在家系S中發(fā)現(xiàn)錯義突變c.2540AG(p.Y847C),編碼氨基酸發(fā)生變化,由酪氨酸變?yōu)榘腚装彼?對照組未見此變異,既往研究未見報道,應(yīng)用軟件Sift、Polyphen-2和Mutation Taster對其進(jìn)行預(yù)測,結(jié)果均顯示有害,應(yīng)用Clustal Omega軟件分析發(fā)現(xiàn)Y847氨基酸在物種進(jìn)化中相對保守,認(rèn)為c.2540AG(p.Y847C)是致病突變。家系S中患者的主要臨床特征是痙攣性斜頸和肌張力障礙性震顫。先證者中未檢測到GNAL基因突變。 結(jié)論 本研究對中國漢族20個原發(fā)性痙攣性斜頸家系進(jìn)行CIZl、ANO3、GNAL基因突變篩查,結(jié)果在家系S中發(fā)現(xiàn)AN03基因新的致病突變：c.2540AG(p.Y847C),突變頻率為5%(1/20)。未見CIZl和GNAL基因致病突變,認(rèn)為CIZ1和GNAL基因突變非中國漢族痙攣性斜頸家系的常見原因。 背景 肌張力障礙(dystonia)(包括扭轉(zhuǎn)痙攣、眼瞼痙攣、口下頜肌張力障礙、痙攣性斜頸、痙攣性構(gòu)音障礙、書寫痙攣等)是一類病理生理復(fù)雜、機(jī)制未明的運(yùn)動障礙病。臨床以肌肉不自主收縮為特征,常導(dǎo)致扭轉(zhuǎn)、重復(fù)性運(yùn)動或異常姿勢,部分患者僅表現(xiàn)為震顫。研究顯示感覺運(yùn)動皮層的可塑性異�？赡軈⑴c肌張力障礙的發(fā)生。腦源性神經(jīng)生長因子(brain-derived neurotrophic factor, BDNF)是突觸和神經(jīng)可塑性的重要調(diào)節(jié)因子,BDNF基因中的單核苷酸多態(tài)性Val66Met (G196A)可能與肌張力障礙相關(guān),但各個研究結(jié)果不一致。 目的 探討B(tài)DNF基因Val66Met (rs6265)多態(tài)性與我國原發(fā)性肌張力障礙間的相關(guān)性。 方法 納入就診于北京協(xié)和醫(yī)院神經(jīng)內(nèi)科運(yùn)動障礙病門診的原發(fā)性肌張力障礙患者252例,同時招募214例既往健康、無神經(jīng)系統(tǒng)疾病、性別年齡與患者相匹配的健康體檢者作為對照組,留取外周血提取基因組DNA。采用SNaPshot技術(shù)對BDNF基因中Val66Met (rs6265)多態(tài)性進(jìn)行檢測。用SPSS13.0統(tǒng)計軟件進(jìn)行數(shù)據(jù)處理,運(yùn)用方差分析驗證組間基因型及等位基因分布差異。 結(jié)果 本研究對中國252例原發(fā)性肌張力障礙患者和214例健康對照進(jìn)行BDNF基因Val66Met (rs6265)多態(tài)性檢測,結(jié)果發(fā)現(xiàn)原發(fā)性肌張力障礙組與對照組、痙攣性斜頸組和對照組之間基因型和等位基因分布無統(tǒng)計學(xué)差異(P值分別為0.309和0.803),各基因型組別之間起病年齡也未見明顯差異(P0.05)。結(jié)論 本研究在中國原發(fā)性肌張力障礙和健康人群中進(jìn)行BDNF基因Val66Met(rs6265)多態(tài)性檢測,結(jié)果未發(fā)現(xiàn)兩者基因型和等位基因分布存在統(tǒng)計學(xué)差異(P0.05),提示Val66Met (rs6265)多態(tài)性與中國原發(fā)性肌張力障礙無相關(guān)性,非中國原發(fā)性肌張力障礙人群的遺傳易感因素。
[Abstract]:background
Dystonia (dystonia) (including torsional spasm, blepharospasm, dyspomia, spasmodic torticollis, spasmodic dysarthria, writing spasm, etc.) is a kind of pathophysiological complex, dysfunctional dyskinesia. Clinical symptoms are characterized by involuntary contraction of muscles, often causing torsion, repetitive movement or abnormal posture, and partial suffering. So far, more than 20 genes in the world have been found to be related to the primary dystonia, in which the DYT25/GNAL gene was found in 2012, and the research at home and abroad is in the initial stage, and there is still a lack of large population research at home.
objective
This study aims to screen the GNAL gene mutation in a large sample of Chinese patients with primary dystonia and to identify the frequency of GNAL gene mutation and the common mutation loci in the people with dystonia in China.
214 patients with primary dystonia (12 cases of positive family history) were enrolled in the Department of Neurology, Peking Union Medical College Hospital, and 100 healthy people were recruited as the control group. The genomic DNA. was extracted from the peripheral blood, and all the 12 exons and 5'UTR regions of the GNAL gene were amplified by PCR, and the products were sequenced and sequenced. The current mutation was screened in the control group by the same method, and the effect of mutation on the protein was predicted by bioinformatics software. At the same time, the GNAL gene mutation screening study at home and abroad was searched to calculate the mutation frequency of the GNAL gene in each study, and the results were compared with the results of the study.
Result
In this study, 214 patients with primary dystonia were screened for GNAL gene mutation. The results showed that 11 variation sites were: c.-37AG, c.-41TC, c.-111CT, c.-116AG, c.-142GC, c.-485TC, c.15CT (p.G5=), c.30GT (p.T10=), c.44GA. C.360CT (p.S120=), c-111CT, c.-41TC, c.-37AG, c.30GT (p.T10=) and c.44GA (p.G15D) are known SNP loci. ) and c.360CT (p.S120=) is synonymous mutation, the encoding amino acid is not changed, considered as a non pathogenic mutation. Mutation Taster was used to predict c.-485TC, c.-142GC, c.-116AG, and the results showed polymorphic change. The frequency of GNAL gene mutation in dystonia patients is quite different from that in 0%-15.38%.
conclusion
In this study, the GNAL gene mutation was screened in 214 patients with primary dystonia in China. The results were not found to be clear, and the GNAL gene mutation was not a common cause of primary dystonia in Chinese people.
background
Cervical dystonia (CD) is the most common focal muscular dystonia in the clinic, which is characterized by involuntary contraction of the neck muscles. The etiology is not clear and genetic factors may be involved. Recent studies have found that the mutations in the DYT23/CIZ1, DYT24/AN03 and DYT25/GNAL genes may be associated with the primary muscle. Dystonia, especially the dystonia of cranioceptic segment, is related to dystonia. There are few studies on the above 3 genes at home and abroad, and there is no genetic study of primary spasmodic torticollis at home.
objective
The purpose of this study was to screen the CIZ1, AN03 and GNAL mutations of primary spasmodic torticollis in Chinese Han population, and to identify the common mutation genes and the frequency of mutation of the familial primary spasmodic torticollis.
Method
20 Chinese Han Primary spasmodic torticollis families were enrolled in the neurology department of Peking Union Medical College Hospital, Peking Union Medical College Hospital, and 100 healthy subjects were recruited as the control group. The genomic DNA. of the peripheral blood was extracted from the peripheral blood, and the whole exon of the AN03.GNAL gene and the 5'UTR region of the GNAL gene were amplified by PCR, and the product was directly produced. The mutations were screened in the control group by the same method, and the effects of the variation on the protein were predicted by the bioinformatics software. The mutation frequencies of the genes in the primary spasmodic torticollis of our country were calculated and compared with the previous research results.
Result
In this study, CIZl, AN03 and GNAL mutations were screened in 20 Chinese primary spasmodic torticollis families. The results showed that two synonymous mutations were found in the CIZ1 gene, c.696GA (p.P232 =) and c.1227CA (p.P409=), the encoded amino acids were not changed, the SNP number was rs45579839 and rs45559035, and the non pathogenic mutation was considered, and the AN03 gene was in the AN03 gene. C.-11GT, c.1158AG (p.L386=), c.1692AC (p.A564=), c.2682CT (p.P894=), c.2478CG, c.2520TG (p.T826=), c.2520TG (p.R840=) and c.2540AG. ) for the known SNP loci, rS143269109, rs2663168, rs11604768 and rs10835051.c.2478CG (p.T826=) and c.2520TG (p.R840=) are synonymous mutations, and the encoded amino acids are not changed. The above 6 variations are considered as non pathogenic mutations. The missense mutagenesis c.2540AG (p.Y847C) is found in the family S, and the coded amino acids change, and the tyrosine changes are changed. For cysteine, no previous study was found in the control group. The application software Sift, Polyphen-2 and Mutation Taster were used to predict it. The results were all harmful. The Clustal Omega software analysis found that the Y847 amino acids were relatively conservative in the evolution of species, and c.2540AG (p.Y847C) was a pathogenic mutation. The main factors in the family S were the patients. The clinical features were spasmodic torticollis and dystonia tremor. No mutations in the GNAL gene were detected in the proband.
conclusion
In this study, the CIZl, ANO3, GNAL gene mutations were screened in 20 Chinese primary spasmodic torticollis families. The results showed a new AN03 gene mutation in family S: c.2540AG (p.Y847C), and the mutation frequency was 5% (1/20). No CIZl and GNAL gene mutations were found, and CIZ1 and GNAL genes were identified as non Chinese Han spasmodic torticollis families. Common reasons.
background
Dystonia (dystonia) (including torsional spasm, blepharospasm, dyspomia, spasmodic torticollis, spasmodic dysarthria, writing spasms, etc.) is a kind of pathophysiological complex, dysfunctional dyskinesia characterized by involuntary contraction of muscles, often causing torsion, repetitive movement or abnormal posture, and partial patients only Brain-derived neurotrophic factor (BDNF) is an important regulator of synapse and nerve plasticity, and the single nucleotide polymorphisms Val66Met (G196A) in the BDNF gene may be associated with dystonia. Guan, but the results of the various studies are inconsistent.
objective
Objective to investigate the correlation between BDNF gene Val66Met (rs6265) polymorphism and primary dystonia in China.
Method
252 patients with primary dystonia in the clinic of Neurology Department of Neurology of Peking Union Medical College Hospital were enrolled, and 214 cases of health, no nervous system disease, sex age and patients matched with healthy persons were recruited as control group, and SNaPshot technique was used for Val66M in the BDNF gene in the BDNF gene of the peripheral blood extraction group. ET (rs6265) polymorphism was detected. Data were processed by SPSS13.0 statistical software. Variance analysis was used to verify the difference of genotype and allele distribution among groups.
Result
In this study, the BDNF gene Val66Met (rs6265) polymorphism was detected in 252 patients with primary dystonia and 214 healthy controls. The results showed that the distribution of genotypes and alleles between the primary dystonia group and the control group had no statistical difference between the spastic torticollis group and the control group (P value was 0.309 and 0.803, respectively). There was no significant difference in age between groups (P0.05).
In this study, the BDNF gene Val66Met (rs6265) polymorphism was detected in Chinese primary dystonia and healthy people. The results were not found to be statistically different between the genotype and allele distribution (P0.05), suggesting that Val66Met (rs6265) polymorphism was not associated with primary dystonia in China and non Chinese primary dystonia. Genetic susceptibility factors of the population.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R746

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