原发性肌张力障碍的遗传学研究
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摘要
背景
肌张力障碍(dystonia)(包括扭转痉挛、眼睑痉挛、口下颌肌张力障碍、痉挛性斜颈、痉挛性构音障碍、书写痉挛等)是一类病理生理复杂、机制未明的运动障碍病。临床症状以肌肉不自主收缩为特征,常导致扭转、重复性运动或异常姿势,部分患者仅表现为震颤。迄今为止,全世界共发现20余种基因与原发性肌张力障碍有关,其中DYT25/GNAL基因于2012年新近发现,国内外对其研究处于初步阶段,国内尚缺乏大规模人群研究。
目的
本研究旨在一个大样本的中国原发性肌张力障碍患者中进行GNAL基因突变筛查,明确我国肌张力障碍人群GNAL基因突变频率及常见突变位点。方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的原发性肌张力障碍患者214例(阳性家族史患者12例),同时募集100例健康者作为对照组,留取外周血提取基因组DNA。对GNAL基因全部12个外显子和5'UTR区进行PCR扩增,产物直接测序。测序发现的变异在对照组中用同样方法进行筛查,并运用生物信息学软件分析预测变异对蛋白的影响。同时检索国内外GNAL基因突变筛查研究,计算各研究中GNAL基因的突变频率,并与本研究结果进行对比。
结果
本研究对214例原发性肌张力障碍患者进行GNAL基因突变筛查,结果发现11个变异位点,分别是：c.-37A>G, c.-41T>C, c.-111C>T, c.-116A>G, c.-142G>C, c.-485T>C, c.15C>T (p.G5=), c.30G>T (p.T10=), c.44G>A (p.G15D), c.1059C>T (p.A353=), c.360C>T (p.S120=)。正常对照组未发现以上变异。其中c.360C>T(p.S120=), c-111C>T, c.-41T>C, c.-37A>G, c.30G>T (p.T10=)和c.44G>A(p.G15D)为已知SNP位点,编号分别为rs76888098, rs61495657, rs9303742, rs200432196, rs78167172和-199761315,认为以上6个变异位点为良性变异,非致病突变。c.15C>T(p.G5=),c.30G>T(1).T10=),c.1059C>T(p.A353=)和c.360C>T(p.S120=)属同义突变,编码氨基酸未发生变化,认为是非致病突变。应用Mutation Taster对c.-485T>C, c.-142G>C, c.-116A>G进行预测,结果显示为多态性改变。总体而言,本研究未发现明确致病突变。对国内外文献进行回顾,不同种族人群中原发性肌张力障碍患者GNAL基因突变频率差异很大,在0%-15.38%不等。
结论
本研究对中国214例原发性肌张力障碍患者进行GNAL基因突变筛查,结果未发现明确致病突变,认为GNAL基因突变非中国人群原发性肌张力障碍的常见致病基因。
背景
痉挛性斜颈(cervical dystonia,CD)是临床上最常见的局灶型肌张力障碍,以颈部肌肉不自主收缩导致头颈部运动和姿势异常为特征。病因尚不明确,遗传因素可能参与其中。最近研究发现,DYT23/CIZ1、DYT24/AN03和DYT25/GNAL基因突变可能与原发性肌张力障碍,特别是颅颈段肌张力障碍相关。目前国内外关于以上3个基因的研究较少,国内尚无原发性痉挛性斜颈家系的遗传学研究。
目的
本研究旨在对中国汉族人群原发性痉挛性斜颈家系进行CIZ1、AN03和GNAL基因突变筛查,明确我国家族性原发性痉挛性斜颈患者的常见突变基因及其突变频率。
方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的中国汉族原发性痉挛性斜颈家系20个,同时募集100名健康受试者作为对照组,留取外周血提取基因组DNA。对先证者的CIZ1、AN03.GNAL基因全部外显子和GNAL基因5'UTR区进行PCR扩增,产物直接测序。测序发现的变异在对照组中用同样方法进行筛查,并运用生物信息学软件分析预测变异对蛋白的影响。计算我国原发性痉挛性斜颈家系各基因的突变频率,并与既往研究结果进行对比。
结果
本研究对中国汉族20个原发性痉挛性斜颈家系进行CIZl、AN03和GNAL基因突变筛查,结果：在CIZ1基因发现两个同义突变,分别为c.696G>A(p.P232＝)和c.1227C>A(p.P409=),编码氨基酸未发生变化,SNP编号为rs45579839和rs45559035,考虑非致病突变；在AN03基因发现7个变异位点,分别为c.-11G>T,c.1158A>G(p.L386=),c.1692A>C(p.A564=),c.2682C>T(p.P894=),c.2478C>G,(p.T826=),c.2520T>G(p.R840=)和c.2540A>G(p.Y847C),健康对照组检测到c.1158A>G(p.L386=),c.1692A>C(p.A564=)和c.2682C>T(p.P894=)。其中c.-11G>T,c.1158A>G(p.L386=),c.1692A>C(p.A564=)和c.2682C>T(p.P894=)为已知SNP位点,编号分别为rS143269109,rs2663168,rs11604768和rs10835051.c.2478C>G(p.T826=)和c.2520T>G(p.R840=)为同义突变,编码氨基酸未发生变化,认为以上6个变异为非致病突变。在家系S中发现错义突变c.2540A>G(p.Y847C),编码氨基酸发生变化,由酪氨酸变为半胱氨酸,对照组未见此变异,既往研究未见报道,应用软件Sift、Polyphen-2和Mutation Taster对其进行预测,结果均显示有害,应用Clustal Omega软件分析发现Y847氨基酸在物种进化中相对保守,认为c.2540A>G(p.Y847C)是致病突变。家系S中患者的主要临床特征是痉挛性斜颈和肌张力障碍性震颤。先证者中未检测到GNAL基因突变。
结论
本研究对中国汉族20个原发性痉挛性斜颈家系进行CIZl、ANO3、GNAL基因突变筛查,结果在家系S中发现AN03基因新的致病突变：c.2540A>G(p.Y847C),突变频率为5%(1/20)。未见CIZl和GNAL基因致病突变,认为CIZ1和GNAL基因突变非中国汉族痉挛性斜颈家系的常见原因。
背景
肌张力障碍(dystonia)(包括扭转痉挛、眼睑痉挛、口下颌肌张力障碍、痉挛性斜颈、痉挛性构音障碍、书写痉挛等)是一类病理生理复杂、机制未明的运动障碍病。临床以肌肉不自主收缩为特征,常导致扭转、重复性运动或异常姿势,部分患者仅表现为震颤。研究显示感觉运动皮层的可塑性异常可能参与肌张力障碍的发生。脑源性神经生长因子(brain-derived neurotrophic factor, BDNF)是突触和神经可塑性的重要调节因子,BDNF基因中的单核苷酸多态性Val66Met (G196A)可能与肌张力障碍相关,但各个研究结果不一致。
目的
探讨BDNF基因Val66Met (rs6265)多态性与我国原发性肌张力障碍间的相关性。
方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的原发性肌张力障碍患者252例,同时招募214例既往健康、无神经系统疾病、性别年龄与患者相匹配的健康体检者作为对照组,留取外周血提取基因组DNA。采用SNaPshot技术对BDNF基因中Val66Met (rs6265)多态性进行检测。用SPSS13.0统计软件进行数据处理,运用方差分析验证组间基因型及等位基因分布差异。
结果
本研究对中国252例原发性肌张力障碍患者和214例健康对照进行BDNF基因Val66Met (rs6265)多态性检测,结果发现原发性肌张力障碍组与对照组、痉挛性斜颈组和对照组之间基因型和等位基因分布无统计学差异(P值分别为0.309和0.803),各基因型组别之间起病年龄也未见明显差异(P>0.05)。结论
本研究在中国原发性肌张力障碍和健康人群中进行BDNF基因Val66Met(rs6265)多态性检测,结果未发现两者基因型和等位基因分布存在统计学差异(P>0.05),提示Val66Met (rs6265)多态性与中国原发性肌张力障碍无相关性,非中国原发性肌张力障碍人群的遗传易感因素。
Backgrounds
Dystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer's cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. The pathogenesis of dystonia is not completely understood. Until now, over20genes have been identified to be associated with primary dystonia among which DYT25/GNAL is newly discovered in2012. The research of GNAL is on its preliminary stage and screening of mutations in GNAL in large number of Chinese patients with primary dystonia is insufficient.
Objectives
We aim to determine the mutation rate and hot spot mutation of GNAL in a large cohort of214Chinese patients with primary dystonia, including12familial cases.
Methods
We recruited214Chinese patients with primary dystonia who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of12exons and5'UTR region of GNAL and mutational screening was performed by direct sequencing. Any mutations identified in the patients were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of GNAL in different populations were calculated by reviewing all published studies screening for mutations of GNAL.
Results
We identified11variants in the12exons and5'UTR region of GNAL:c.-37A>G, c.-41T>C, c.-111C>T, c.-116A>G, c.-142G>C, c.-485T>C, c.15C>T (p.G5=), c.30G>T (p.T10=), c.44G>A (p.G15D), c.1059C>T (p.A353=) and c.360C>T (p.S120=). Among these, c.360C>T(p.S120=), c.-111C>T, c.-41T>C, c.-37A>G, c.30G>T(p.T10=) and c.44G>A (p.G15D) were proved to be SNPs (rs76888098, rs61495657, rs9303742, rs200432196, rs78167172and rs199761315) and were not pathogenic mutations. c.15C>T (p.G5=), c.30G>T (p.T10=), c.1059C>T (p.A353=) and c.360C>T (p.S120=) were synonymous mutations and protein were not changed. Mutation Taster revealed that c.-485T>C, c.-142G>C, c.-116A>G were polymorphism and not pathogenic as well. These variants were not detected in healthy controls. By reviewing the previous studies, we found mutation rates of GNAL varied greatly in different populations, ranging from0%to15.38%.
Conclusions
In summary, we did not identify any mutations in GNAL that could be a cause of the dystonia in214cases drawn from China, including12familial cases. Our own data suggest that GNAL mutations do not represent a common cause of primary dystonia, as least in Chinese population.
Backgrounds
Cervical dystonia (CD), the most common form of primary focal dystonia, is characterized by involuntary muscle contractions of the cervical musculature, leading to twisting or abnormal postures. The cause of cervical dystonia is unknown; however, there is evidence for a genetic component to its etiology. Mutations in CIZ1, ANO3and GNAL have recently been associated with primary dystonia, especially craniocervical dystonia. Until now, there is no genetic study of patients with familial cervical dystonia in China.
Objectives
We aim to determine the mutation rates of CIZ1, ANO3and GNAL in twenty cervical dystonia pedigrees of Chinese Han population.
Methods
We recruited20cervical dystonia pedigrees of Chinese Han population who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of all exons of CIZ1, ANO3and GNAL and5'UTR region of GNAL of20probands. Mutational screening was performed by direct sequencing. Any mutations identified in the probands were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of CIZ1, ANO3and GNAL were calculated in our study.
Results
We identified two synonymous mutations in the CIZ1gene:c.696G>A (p.P232=) and c.1227C>A (p.P409=), which proved to be SNPs rs45579839and rs455590357. Also,7variants were detected in the ANO3gene:c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=), c.2682C>T (p.P894=), c.2478C>G,(p.T826=), c.2520T>G (p.R840=) and c.2540A>G(p.Y847C). Among these, c.1158A>G(p.L386=), c.1692A>C(p.A564=) and c.2682C>T (p.P894=) were also found in the control group. c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=) and c.2682C>T (p.P894=) were proved to be SNPs: rs143269109, rs2663168, rs11604768and rs10835051. c.2478C>G (p.T826=) and c.2520T>G (p.R840=) were synonymous mutations leading no change in amino acids. In addition, a missense mutation, c.2540A>G (p.Y847C) was found in Family S with cervical dystonia and dystonic tremor. This variant was predicted to be damaging by all3programs and not found in previous studies. Clustal Omega analysis of the protein in different species showed mutation conservation. No variants were found in the GNAL gene.
Conclusions
In summary, we identified one missense mutation in AN03, c.2540A>G (p.Y847C) in20cervical dystonia pedigrees in China. No pathogenic mutations were found in CIZ1and GNAL gene. The mutation rate of ANO3gene in familial cervical dystonia patients is5%(1/20). Our study also suggests that mutations in CIZ1and GNAL are not a common cause of familial cervical dystonia, as least in Chinese Han population.
Backgrounds
Dystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer's cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. Brain-derived neurotrophic factor (BDNF) is a modulator of synaptic and neural plasticity. Considering the association between dystonia and abnormal sensorimotor cortex plasticity, BDNF may be a candidate gene that confers susceptibility to dystonia. However, the association between Va166Met polymorphism of BDNF gene and primary dystonia is controversial.
Objectives
We aim to assess the association between the Va166Met polymorphism of BDNF gene and primary dystonia in China.
Methods
A case-control study was performed to evaluate the association between Va166Met polymorphism in the BDNF gene and primary dystonia in a cohort of252Chinese patients and in214age-and gender-matched healthy control subjects. Genotyping was carried out using SNaPshot technology. Data was processed by SPSS13.0and Analysis of Variance (ANOVA) was used to compare the genotype and allele distribution between the groups.
Results
No association was identified between Va166Met polymorphism and primary dystonia or cervical dystonia (P=0.309and P=0.803respectively).In a subsequent subgroup analysis, there was also no difference in the distribution for age of onset.
Conclusions
Our findings do not support that Va166Met polymorphism of BDNF gene contributes to the risk of primary dystonia in China.
肌张力障碍(dystonia)(包括扭转痉挛、眼睑痉挛、口下颌肌张力障碍、痉挛性斜颈、痉挛性构音障碍、书写痉挛等)是一类病理生理复杂、机制未明的运动障碍病。临床症状以肌肉不自主收缩为特征,常导致扭转、重复性运动或异常姿势,部分患者仅表现为震颤。迄今为止,全世界共发现20余种基因与原发性肌张力障碍有关,其中DYT25/GNAL基因于2012年新近发现,国内外对其研究处于初步阶段,国内尚缺乏大规模人群研究。
目的
本研究旨在一个大样本的中国原发性肌张力障碍患者中进行GNAL基因突变筛查,明确我国肌张力障碍人群GNAL基因突变频率及常见突变位点。方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的原发性肌张力障碍患者214例(阳性家族史患者12例),同时募集100例健康者作为对照组,留取外周血提取基因组DNA。对GNAL基因全部12个外显子和5'UTR区进行PCR扩增,产物直接测序。测序发现的变异在对照组中用同样方法进行筛查,并运用生物信息学软件分析预测变异对蛋白的影响。同时检索国内外GNAL基因突变筛查研究,计算各研究中GNAL基因的突变频率,并与本研究结果进行对比。
结果
本研究对214例原发性肌张力障碍患者进行GNAL基因突变筛查,结果发现11个变异位点,分别是：c.-37A>G, c.-41T>C, c.-111C>T, c.-116A>G, c.-142G>C, c.-485T>C, c.15C>T (p.G5=), c.30G>T (p.T10=), c.44G>A (p.G15D), c.1059C>T (p.A353=), c.360C>T (p.S120=)。正常对照组未发现以上变异。其中c.360C>T(p.S120=), c-111C>T, c.-41T>C, c.-37A>G, c.30G>T (p.T10=)和c.44G>A(p.G15D)为已知SNP位点,编号分别为rs76888098, rs61495657, rs9303742, rs200432196, rs78167172和-199761315,认为以上6个变异位点为良性变异,非致病突变。c.15C>T(p.G5=),c.30G>T(1).T10=),c.1059C>T(p.A353=)和c.360C>T(p.S120=)属同义突变,编码氨基酸未发生变化,认为是非致病突变。应用Mutation Taster对c.-485T>C, c.-142G>C, c.-116A>G进行预测,结果显示为多态性改变。总体而言,本研究未发现明确致病突变。对国内外文献进行回顾,不同种族人群中原发性肌张力障碍患者GNAL基因突变频率差异很大,在0%-15.38%不等。
结论
本研究对中国214例原发性肌张力障碍患者进行GNAL基因突变筛查,结果未发现明确致病突变,认为GNAL基因突变非中国人群原发性肌张力障碍的常见致病基因。
背景
痉挛性斜颈(cervical dystonia,CD)是临床上最常见的局灶型肌张力障碍,以颈部肌肉不自主收缩导致头颈部运动和姿势异常为特征。病因尚不明确,遗传因素可能参与其中。最近研究发现,DYT23/CIZ1、DYT24/AN03和DYT25/GNAL基因突变可能与原发性肌张力障碍,特别是颅颈段肌张力障碍相关。目前国内外关于以上3个基因的研究较少,国内尚无原发性痉挛性斜颈家系的遗传学研究。
目的
本研究旨在对中国汉族人群原发性痉挛性斜颈家系进行CIZ1、AN03和GNAL基因突变筛查,明确我国家族性原发性痉挛性斜颈患者的常见突变基因及其突变频率。
方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的中国汉族原发性痉挛性斜颈家系20个,同时募集100名健康受试者作为对照组,留取外周血提取基因组DNA。对先证者的CIZ1、AN03.GNAL基因全部外显子和GNAL基因5'UTR区进行PCR扩增,产物直接测序。测序发现的变异在对照组中用同样方法进行筛查,并运用生物信息学软件分析预测变异对蛋白的影响。计算我国原发性痉挛性斜颈家系各基因的突变频率,并与既往研究结果进行对比。
结果
本研究对中国汉族20个原发性痉挛性斜颈家系进行CIZl、AN03和GNAL基因突变筛查,结果：在CIZ1基因发现两个同义突变,分别为c.696G>A(p.P232＝)和c.1227C>A(p.P409=),编码氨基酸未发生变化,SNP编号为rs45579839和rs45559035,考虑非致病突变；在AN03基因发现7个变异位点,分别为c.-11G>T,c.1158A>G(p.L386=),c.1692A>C(p.A564=),c.2682C>T(p.P894=),c.2478C>G,(p.T826=),c.2520T>G(p.R840=)和c.2540A>G(p.Y847C),健康对照组检测到c.1158A>G(p.L386=),c.1692A>C(p.A564=)和c.2682C>T(p.P894=)。其中c.-11G>T,c.1158A>G(p.L386=),c.1692A>C(p.A564=)和c.2682C>T(p.P894=)为已知SNP位点,编号分别为rS143269109,rs2663168,rs11604768和rs10835051.c.2478C>G(p.T826=)和c.2520T>G(p.R840=)为同义突变,编码氨基酸未发生变化,认为以上6个变异为非致病突变。在家系S中发现错义突变c.2540A>G(p.Y847C),编码氨基酸发生变化,由酪氨酸变为半胱氨酸,对照组未见此变异,既往研究未见报道,应用软件Sift、Polyphen-2和Mutation Taster对其进行预测,结果均显示有害,应用Clustal Omega软件分析发现Y847氨基酸在物种进化中相对保守,认为c.2540A>G(p.Y847C)是致病突变。家系S中患者的主要临床特征是痉挛性斜颈和肌张力障碍性震颤。先证者中未检测到GNAL基因突变。
结论
本研究对中国汉族20个原发性痉挛性斜颈家系进行CIZl、ANO3、GNAL基因突变筛查,结果在家系S中发现AN03基因新的致病突变：c.2540A>G(p.Y847C),突变频率为5%(1/20)。未见CIZl和GNAL基因致病突变,认为CIZ1和GNAL基因突变非中国汉族痉挛性斜颈家系的常见原因。
背景
肌张力障碍(dystonia)(包括扭转痉挛、眼睑痉挛、口下颌肌张力障碍、痉挛性斜颈、痉挛性构音障碍、书写痉挛等)是一类病理生理复杂、机制未明的运动障碍病。临床以肌肉不自主收缩为特征,常导致扭转、重复性运动或异常姿势,部分患者仅表现为震颤。研究显示感觉运动皮层的可塑性异常可能参与肌张力障碍的发生。脑源性神经生长因子(brain-derived neurotrophic factor, BDNF)是突触和神经可塑性的重要调节因子,BDNF基因中的单核苷酸多态性Val66Met (G196A)可能与肌张力障碍相关,但各个研究结果不一致。
目的
探讨BDNF基因Val66Met (rs6265)多态性与我国原发性肌张力障碍间的相关性。
方法
纳入就诊于北京协和医院神经内科运动障碍病门诊的原发性肌张力障碍患者252例,同时招募214例既往健康、无神经系统疾病、性别年龄与患者相匹配的健康体检者作为对照组,留取外周血提取基因组DNA。采用SNaPshot技术对BDNF基因中Val66Met (rs6265)多态性进行检测。用SPSS13.0统计软件进行数据处理,运用方差分析验证组间基因型及等位基因分布差异。
结果
本研究对中国252例原发性肌张力障碍患者和214例健康对照进行BDNF基因Val66Met (rs6265)多态性检测,结果发现原发性肌张力障碍组与对照组、痉挛性斜颈组和对照组之间基因型和等位基因分布无统计学差异(P值分别为0.309和0.803),各基因型组别之间起病年龄也未见明显差异(P>0.05)。结论
本研究在中国原发性肌张力障碍和健康人群中进行BDNF基因Val66Met(rs6265)多态性检测,结果未发现两者基因型和等位基因分布存在统计学差异(P>0.05),提示Val66Met (rs6265)多态性与中国原发性肌张力障碍无相关性,非中国原发性肌张力障碍人群的遗传易感因素。
Backgrounds
Dystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer's cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. The pathogenesis of dystonia is not completely understood. Until now, over20genes have been identified to be associated with primary dystonia among which DYT25/GNAL is newly discovered in2012. The research of GNAL is on its preliminary stage and screening of mutations in GNAL in large number of Chinese patients with primary dystonia is insufficient.
Objectives
We aim to determine the mutation rate and hot spot mutation of GNAL in a large cohort of214Chinese patients with primary dystonia, including12familial cases.
Methods
We recruited214Chinese patients with primary dystonia who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of12exons and5'UTR region of GNAL and mutational screening was performed by direct sequencing. Any mutations identified in the patients were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of GNAL in different populations were calculated by reviewing all published studies screening for mutations of GNAL.
Results
We identified11variants in the12exons and5'UTR region of GNAL:c.-37A>G, c.-41T>C, c.-111C>T, c.-116A>G, c.-142G>C, c.-485T>C, c.15C>T (p.G5=), c.30G>T (p.T10=), c.44G>A (p.G15D), c.1059C>T (p.A353=) and c.360C>T (p.S120=). Among these, c.360C>T(p.S120=), c.-111C>T, c.-41T>C, c.-37A>G, c.30G>T(p.T10=) and c.44G>A (p.G15D) were proved to be SNPs (rs76888098, rs61495657, rs9303742, rs200432196, rs78167172and rs199761315) and were not pathogenic mutations. c.15C>T (p.G5=), c.30G>T (p.T10=), c.1059C>T (p.A353=) and c.360C>T (p.S120=) were synonymous mutations and protein were not changed. Mutation Taster revealed that c.-485T>C, c.-142G>C, c.-116A>G were polymorphism and not pathogenic as well. These variants were not detected in healthy controls. By reviewing the previous studies, we found mutation rates of GNAL varied greatly in different populations, ranging from0%to15.38%.
Conclusions
In summary, we did not identify any mutations in GNAL that could be a cause of the dystonia in214cases drawn from China, including12familial cases. Our own data suggest that GNAL mutations do not represent a common cause of primary dystonia, as least in Chinese population.
Backgrounds
Cervical dystonia (CD), the most common form of primary focal dystonia, is characterized by involuntary muscle contractions of the cervical musculature, leading to twisting or abnormal postures. The cause of cervical dystonia is unknown; however, there is evidence for a genetic component to its etiology. Mutations in CIZ1, ANO3and GNAL have recently been associated with primary dystonia, especially craniocervical dystonia. Until now, there is no genetic study of patients with familial cervical dystonia in China.
Objectives
We aim to determine the mutation rates of CIZ1, ANO3and GNAL in twenty cervical dystonia pedigrees of Chinese Han population.
Methods
We recruited20cervical dystonia pedigrees of Chinese Han population who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of all exons of CIZ1, ANO3and GNAL and5'UTR region of GNAL of20probands. Mutational screening was performed by direct sequencing. Any mutations identified in the probands were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of CIZ1, ANO3and GNAL were calculated in our study.
Results
We identified two synonymous mutations in the CIZ1gene:c.696G>A (p.P232=) and c.1227C>A (p.P409=), which proved to be SNPs rs45579839and rs455590357. Also,7variants were detected in the ANO3gene:c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=), c.2682C>T (p.P894=), c.2478C>G,(p.T826=), c.2520T>G (p.R840=) and c.2540A>G(p.Y847C). Among these, c.1158A>G(p.L386=), c.1692A>C(p.A564=) and c.2682C>T (p.P894=) were also found in the control group. c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=) and c.2682C>T (p.P894=) were proved to be SNPs: rs143269109, rs2663168, rs11604768and rs10835051. c.2478C>G (p.T826=) and c.2520T>G (p.R840=) were synonymous mutations leading no change in amino acids. In addition, a missense mutation, c.2540A>G (p.Y847C) was found in Family S with cervical dystonia and dystonic tremor. This variant was predicted to be damaging by all3programs and not found in previous studies. Clustal Omega analysis of the protein in different species showed mutation conservation. No variants were found in the GNAL gene.
Conclusions
In summary, we identified one missense mutation in AN03, c.2540A>G (p.Y847C) in20cervical dystonia pedigrees in China. No pathogenic mutations were found in CIZ1and GNAL gene. The mutation rate of ANO3gene in familial cervical dystonia patients is5%(1/20). Our study also suggests that mutations in CIZ1and GNAL are not a common cause of familial cervical dystonia, as least in Chinese Han population.
Backgrounds
Dystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer's cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. Brain-derived neurotrophic factor (BDNF) is a modulator of synaptic and neural plasticity. Considering the association between dystonia and abnormal sensorimotor cortex plasticity, BDNF may be a candidate gene that confers susceptibility to dystonia. However, the association between Va166Met polymorphism of BDNF gene and primary dystonia is controversial.
Objectives
We aim to assess the association between the Va166Met polymorphism of BDNF gene and primary dystonia in China.
Methods
A case-control study was performed to evaluate the association between Va166Met polymorphism in the BDNF gene and primary dystonia in a cohort of252Chinese patients and in214age-and gender-matched healthy control subjects. Genotyping was carried out using SNaPshot technology. Data was processed by SPSS13.0and Analysis of Variance (ANOVA) was used to compare the genotype and allele distribution between the groups.
Results
No association was identified between Va166Met polymorphism and primary dystonia or cervical dystonia (P=0.309and P=0.803respectively).In a subsequent subgroup analysis, there was also no difference in the distribution for age of onset.
Conclusions
Our findings do not support that Va166Met polymorphism of BDNF gene contributes to the risk of primary dystonia in China.
引文
[1]Klein C, Ozelius LJ. Dystonia:clinical features, genetics, and treatment[J]. Curr Opin Neurol.2002.15(4):491-7.
[2]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008.41(8)：570-573.
[3]汤晓芙,万新华,黄光.A型肉毒毒素治疗局限性肌张力障碍和肌肉痉挛[J].中华神经科杂志.1999.32(3)：135.
[4]Muller U, Steinberger D, Nemeth AH. Clinical and molecular genetics of primary dystonias. Neurogenetics[J].1998.1(3):165-77.
[5]Nemeth AH. The genetics of primary dystonias and related disorders[J]. Brain. 2002.125(Pt 4):695-721.
[6]LeDoux MS. The genetics of dystonias[J]. Adv Genet.2012.79:35-85.
[7]Defazio G, Abbruzzese G, Girlanda P, et al. Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia[J]. J Neurol.2012.259(11): 2414-8.
[8]Fletcher NA. The genetics of idiopathic torsion dystonia[J]. J Med Genet.1990. 27(7):409-12.
[9]Muller U, Kupke KG. The genetics of primary torsion dystonia[J]. Hum Genet. 1990.84(2):107-15.
[10]de Carvalho Aguiar PM, Ozelius LJ. Classification and genetics of dystonia[J]. Lancet Neurol.2002.1(5):316-25.
[11]Defazio G, Abbruzzese G, Livrea P, Berardelli A. Epidemiology of primary dystonia[J]. Lancet Neurol.2004.3(11):673-8.
[12]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013.45(1):88-92.
[13]Vemula SR, Puschmann A, Xiao J, et al. Role of Galpha(olf) in familial and sporadic adult-onset primary dystonia[J]. Hum Mol Genet.2013.22(12):2510-9.
[14]Herve D, Levi-Strauss M, Marey-Semper I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993.13(5):2237-48.
[15]Drinnan SL, Hope BT, Snutch TP, Vincent SR. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991.2(1):66-70.
[16]Kull B, Svenningsson P, Fredholm BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000. 58(4):771-7.
[17]Herve D, Le MC, Corvol JC, et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum[J]. J Neurosci. 2001.21(12):4390-9.
[18]Corvol JC, Studler JM, Schonn JS, Girault JA, Herve D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum[J]. J Neurochem.2001.76(5):1585-8.
[19]Miao J, Wan XH, Sun Y, Feng JC, Cheng FB. Mutation screening of GNAL gene in patients with primary dystonia from Northeast China[J]. Parkinsonism Relat Disord.2013.19(10):910-2.
[20]Kumar KR, Lohmann K, Masuho I, et al. Mutations in GNAL:A Novel Cause of Craniocervical Dystonia.LID-10.1001/jamaneurol.2013.4677 [doi]. JAMA Neurol.2014.
[21]Fahn S, Bressman SB, Marsden CD. Classification of dystonia[J]. Adv Neurol. 1998.78:1-10.
[22]Dufke C, Sturm M, Schroeder C, et al. Screening of mutations in GNAL in sporadic dystonia patients.LID-10.1002/mds.25794 [doi]. Mov Disord.2014.
[23]Saunders-Pullman R, Fuchs T, San LM, et al. Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.LID-10.1002/mds.25818 [doi]. Mov Disord.2014.
[24]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014.29(1): 143-7.
[25]Charlesworth G, Bhatia KP, Wood NW. No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia[J]. Mov Disord.2014.29(1): 154-5.
[26]Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G. Sporadic focal dystonia in northwest Germany:molecular basis on chromosome 18p[J]. Ann Neurol.1997.42(1):111-4.
[27]Awaad Y, Munoz S, Nigro M. Progressive dystonia in a child with chromosome 18p deletion, treated with intrathecal baclofen[J]. J Child Neurol.1999.14(2): 75-7.
[28]Bhidayasiri R, Jen JC, Baloh RW. Three brothers with a very-late-onset writer's cramp[J]. Mov Disord.2005.20(10):1375-7.
[29]Graziadio C, Rosa RF, Zen PR, Pinto LL, Barea LM, Paskulin GA. Dystonia, autoimmune disease and cerebral white matter abnormalities in a patient with 18p deletion[J]. Arq Neuropsiquiatr.2009.67(3A):689-91.
[30]Kowarik MC, Langer S, Keri C, Hemmer B, Oexle K, Winkelmann J. Myoclonus-dystonia in 18p deletion syndrome[J]. Mov Disord.2011.26(3): 560-1.
[31]Nasir J, Frima N, Pickard B, Malloy MP, Zhan L, Grunewald R. Unbalanced whole arm translocation resulting in loss of 18p in dystoni[J]a. Mov Disord.2006. 21(6):859-63.
[32]Postma AG, Verschuuren-Bemelmans CC, Kok K, van Laar T. Characteristics of dystonia in the 18p deletion syndrome, including a new case[J]. Clin Neurol Neurosurg.2009.111(10):880-2.
[33]Tezzon F, Zanoni T, Passarin MG, Ferrari G. Dystonia in a patient with deletion of 18p[J]. Ital J Neurol Sci.1998.19(2):90-3.
[34]Leube B, Rudnicki D, Ratzlaff T, Kessler KR, Benecke R, Auburger G. Idiopathic torsion dystonia:assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distributionfJ]. Hum Mol Genet.1996.5(10):1673-7.
[35]Klein C, Ozelius LJ, Hagenah J, Breakefield XO, Risch NJ, Vieregge P. Search for a founder mutation in idiopathic focal dystonia from Northern Germany [J]. Am J Hum Genet.1998.63(6):1777-82.
[36]Regnauld KL, Leteurtre E, Gutkind SJ, Gespach CP, Emami S. Activation of adenylyl cyclases, regulation of insulin status, and cell survival by G(alpha)olf in pancreatic beta-cells[J]. Am J Physiol Regul Integr Comp Physiol.2002. 282(3):R870-80.
[37]Wackym PA, Cioffi JA, Erbe CB, Popper P. G-protein Golfalpha (GNAL) is expressed in the vestibular end organs and primary afferent neurons of Rattus norvegicus[J]. J Vestib Res.2005.15(1):11-5.
[38]Belluscio L, Gold GH, Nemes A, Axel R. Mice deficient in G(olf) are anosmic[J]. Neuron.1998.20(1):69-81.
[39]Ghadami M, Majidzadeh-A K, Morovvati S, et al. Isolated congenital anosmia with morphologically normal olfactory bulb in two Iranian families:a new clinical entity[J]. Am J Med Genet A.2004.127A(3):307-9.
[40]Wang XZ, Zhong N. Clinical and genetic features of DYT1 and DYT5[J]. Beijing Da Xue Xue Bao.2006.38(1):107-9.
[41]Naiya T, Biswas A, Neogi R, et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients[J]. Acta Neurol Scand.2006. 114(3):210-5.
[42]Zhang SS, Fang DF, Hu XH, et al. Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China[J]. Eur J Neurol.2010.17(6): 846-51.
[43]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[44]Akbari MT, Zand Z, Shahidi GA, Hamid M. Clinical features, DYT1 mutation screening and genotype-phenotype correlation in patients with dystonia from Iran[J]. Med Princ Pract.2012.21(5):462-6.
[45]王琳,万新华,成伏波,杨英麦,马凌燕,崔丽英.DYT6型肌张力障碍患者的临床表现和影像学特点[J].中华神经科杂志.2013.46(3)：148-152.
[46]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[47]Miyamoto R, Koizumi H, Morino H, et al. DYT6 in Japan-genetic screening and clinical characteristics of the patients[J]. Mov Disord.2014.29(2):278-80.
[1]Jankovic J, Leder S, Warner D, et al. Cervical dystonia:clinical findings and associated movement disorders[J]. Neurology,1991,41(7):1088-91.
[2]Nutt JG, Muenter MD, Aronson A, et al. Epidemiology of focal and generalized dystonia in Rochester, Minnesota[J]. Mov Disord,1988,3(3):188-94.
[3]A prevalence study of primary dystonia in eight European countries[J]. J Neurol, 2000,247(10):787-92.
[4]Duffey PO, Butler AG, Hawthorne MR, et al. The epidemiology of the primary dystonias in the north of England[J]. Adv Neurol,1998,78:121-5.
[5]Velickovic M, Benabou R, Brin MF. Cervical dystonia pathophysiology and treatment options[J]. Drugs,2001,61(13):1921-43.
[6]Jahanshahi M, Marion MH, Marsden CD. Natural history of adult-onset idiopathic torticollis[J]. Arch Neurol,1990,47(5):548-52.
[7]Jahanshahi M. Factors that ameliorate or aggravate spasmodic torticollis[J]. J Neurol Neurosurg Psychiatry,2000,68(2):227-9.
[8]Poisson A, Krack P, Thobois S, et al. History of the'geste antagoniste'sign in cervical dystonia[J]. J Neurol,2012.
[9]Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence variants in primary dystonia[J]. Neurology.2010.74(3):229-38.
[10]Muller U. The monogenic primary dystonias[J]. Brain,2009,132(Pt 8):2005-25.
[11]Petrucci S, Valente EM. Genetic issues in the diagnosis of dystonias. Front Neurol. 2013.4:34.
[12]Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families[J]. Ann Neurol,1997,42(4):670-3.
[13]Cheng FB, Wan XH, Feng JC, et al. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol,2011,18(3):497-503.
[14]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China [J]. Eur J Neurol.2011. 18(3):497-503.
[15]Leube B, Hendgen T, Kessler KR, et al. Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe[J]. Am J Med Genet, 1997,74(5):529-32.
[16]Xiao J, Uitti RJ, Zhao Y, et al. Mutations in CIZ1 cause adult onset primary cervical dystonia[J]. Ann Neurol,2012,71(4):458-69.
[17]Charlesworth G, Plagnol V, Holmstrom KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012.91(6):1041-50.
[18]Kang HJ, Kawasawa YI, Cheng F, et al. Spatio-temporal transcriptome of the human brain[J]. Nature.2011.478(7370):483-9.
[19]Johnson MB, Kawasawa YI, Mason CE, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis[J]. Neuron.2009.62(4):494-509.
[20]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013.45(1):88-92.
[21]Ma L, Chen R, Wang L, Yang Y, Wan X. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013.28(13): 1899-901.
[22]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014.29(1): 143-7.
[23]Stamelou M, Charlesworth G, Cordivari C, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations.LID-10.1002/mds.25802 [doi]. Mov Disord. 2014.
[24]Hopfner F, Bungeroth M, Pendziwiat M, et al. Rare variants in ANO3 are not a susceptibility factor in essential tremor[J]. Parkinsonism Relat Disord.2014. 20(1):134-5.
[25]Herve D, Levi-Strauss M, Marey-Semper I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993.13(5):2237-48.
[26]Drinnan SL, Hope BT, Snutch TP, Vincent SR. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991.2(1):66-70.
[27]Kull B, Svenningsson P, Fredholm BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000. 58(4):771-7.
[28]Herve D, Le MC, Corvol JC, et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum[J]. J Neurosci. 2001.21(12):4390-9.
[29]Corvol JC, Studler JM, Schonn JS, Girault JA, Herve D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum[J]. J Neurochem.2001.76(5):1585-8.
[30]Vemula SR, Puschmann A, Xiao J, et al. Role of Galpha(olf) in familial and sporadic adult-onset primary dystonia[J]. Hum Mol Genet.2013.22(12):2510-9.
[31]Charlesworth G, Bhatia KP, Wood NW. No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia[J]. Mov Disord.2014.29(1): 154-5.
[1]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008.41(8)：570-573.
[2]Klein C, Ozelius LJ. Dystonia:clinical features, genetics, and treatment[J]. Curr Opin Neurol.2002.15(4):491-7.
[3]Defazio G, Abbruzzese G, Girlanda P, et al. Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia[J]. J Neurol.2012.259(11): 2414-8.
[4]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[5]Ma L, Chen R, Wang L, Yang Y, Wan X. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013.28(13): 1899-901.
[6]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls [J]. Mov Disord.2014.29(1): 143-7.
[7]Charlesworth G, Plagnol V, Holmstrom KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012.91(6):1041-50.
[8]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystoni[J]a. Nat Genet.2013.45(1):88-92.
[9]Kaur A. Rare autosomal dominant mutations in GNAL are associated with primary torsion dystonia[J]. Clin Genet.2013.84(3):211-2.
[10]Miao J, Wan XH, Sun Y, Feng JC, Cheng FB. Mutation screening of GNAL gene in patients with primary dystonia from Northeast China[J]. Parkinsonism Relat Disord.2013.19(10):910-2.
[11]Saunders-Pullman R, Fuchs T, San LM, et al. Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.LID 10.1002/mds.25818 [doi]. Mov Disord.2014.
[12]Defazio G, Berardelli A, Hallett M. Do primary adult-onset focal dystonias share aetiological factors[J]. Brain.2007.130(Pt 5):1183-93.
[13]Sharma N, Franco RA Jr, Kuster JK, et al. Genetic evidence for an association of the TOR1A locus with segmental/focal dystoni[J]a. Mov Disord.2010.25(13): 2183-7.
[14]Chen Y, Song W, Yang J, et al. Association of the Va166Met polymorphism of the BDNF gene with primary cranial-cervical dystonia patients from South-west China[J]. Parkinsonism Relat Disord.2013.19(11):1043-5.
[15]Cramer SC, Sampat A, Haske-Palomino M, Nguyen S, Procaccio V, Hermanowicz N. Increased prevalence of val(66)met BDNF genotype among subjects with cervical dystonia[J]. Neurosci Lett.2010.468(1):42-5.
[16]Hallett M. Dystonia:a sensory and motor disorder of short latency inhibition[J]. Ann Neurol.2009.66(2):125-7.
[17]Kaji R. Basal ganglia as a sensory gating devise for motor control[J]. J Med Invest.2001.48(3-4):142-6.
[18]Quartarone A, Morgante F, Sant'angelo A, et al. Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia[J]. J Neurol Neurosurg Psychiatry.2008.79(9):985-90.
[19]Beck S, Richardson SP, Shamim EA, Dang N, Schubert M, Hallett M. Short intracortical and surround inhibition are selectively reduced during movement initiation in focal hand dystonia[J]. J Neurosci.2008.28(41):10363-9.
[20]Sohn YH, Hallett M. Disturbed surround inhibition in focal hand dystonia[J]. Ann Neurol.2004.56(4):595-9.
[21]Quartarone A, Sant'Angelo A, Battaglia F, et al. Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm[J]. J Neurosci.2006.26(2):716-21.
[22]Rothwell J. Transcranial magnetic stimulation as a method for investigating the plasticity of the brain in Parkinson's disease and dystonia[J]. Parkinsonism Relat Disord.2007.13 Suppl 3:S417-20.
[23]Tempel LW, Perlmutter JS. Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia[J]. Brain.1990.113 (Pt 3):691-707.
[24]Murase N, Shimadu H, Urushihara R, Kaji R. Abnormal sensorimotor integration in hand dystonia[J]. Suppl Clin Neurophysiol.2006.59:283-7.
[25]Cheeran B, Talelli P, Mori F, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS[J]. J Physiol.2008.586(Pt 23):5717-25.
[26]Lipsky RH, Marini AM. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity[J]. Ann NY Acad Sci.2007.1122:130-43.
[27]Cotman CW, Berchtold NC. Exercise:a behavioral intervention to enhance brain health and plasticity [J]. Trends Neurosci.2002.25(6):295-301.
[28]Lu B. BDNF and activity-dependent synaptic modulation[J]. Learn Mem.2003. 10(2):86-98.
[29]Klintsova AY, Dickson E, Yoshida R, Greenough WT. Altered expression of BDNF and its high-affinity receptor TrkB in response to complex motor learning and moderate exercise[J]. Brain Res.2004.1028(1):92-104.
[30]Egan MF, Kojima M, Callicott JH, et al. The BDNF va166met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function[J]. Cell.2003.112(2):257-69.
[31]Pezawas L, Verchinski BA, Mattay VS, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology[J]. J Neurosci.2004.24(45):10099-102.
[32]Hariri AR, Goldberg TE, Mattay VS, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance[J]. J Neurosci.2003.23(17):6690-4.
[33]Kleim JA, Chan S, Pringle E, et al. BDNF va166met polymorphism is associated with modified experience-dependent plasticity in human motor cortex[J]. Nat Neurosci.2006.9(6):735-7.
[34]Martino D, Muglia M, Abbruzzese G, et al. Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia[J]. Eur J Neurol.2009. 16(8):949-52.
[35]Groen JL, Ritz K, Velseboer DC, et al. Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia.LID-10.1002/mds.24922 [doi]. Mov Disord.2012.
[36]Svetel MV, Djuric G, Novakovic I, et al. A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia[J]. Acta Neurol Belg.2013.113(3):243-5.
[37]Fahn S, Bressman SB, Marsden CD. Classification of dystonia[J]. Adv Neurol. 1998.78:1-10.
[38]Lu B. BDNF and activity-dependent synaptic modulation[J]. Learn Mem.2003. 10(2):86-98.
[39]Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action[J]. Nat Rev Neurosci.2005.6(8):603-14.
[40]Hong CJ, Liou YJ, Tsai SJ. Effects of BDNF polymorphisms on brain function and behavior in health and disease[J]. Brain Res Bull.2011.86(5-6):287-97.
[41]Opal P, Tintner R, Jankovic J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia:from asymptomatic TOR1A gene carrier status to dystonic storm[J]. Mov Disord.2002.17(2):339-45.
[42]Karamohamed S, Latourelle JC, Racette BA, et al. BDNF genetic variants are associated with onset age of familial Parkinson disease:GenePD Study[J]. Neurology.2005.65(11):1823-5.
[43]Voineskos AN, Lerch JP, Felsky D, et al. The brain-derived neurotrophic factor Va166Met polymorphism and prediction of neural risk for Alzheimer disease[J]. Arch Gen Psychiatry.2011.68(2):198-206.
[44]Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study[J]. Am J Hum Genet.2002.71(3): 651-5.
[1]Klein, C, Ozelius, LJ. Dystonia:clinical features, genetics, and treatment[J]. Curr Opin Neurol.2002,15(4):491-7.
[2]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008,41(8)：570-573.
[3]汤晓芙,万新华,黄光.A型肉毒毒素治疗局限性肌张力障碍和肌肉痉挛[J].中华神经科杂志.1999,32(3)：135.
[4]Muller, U. The monogenic primary dystonias[J]. Brain.2009,132(Pt 8):2005-25.
[5]Ozelius, LJ, Hewett, JW, Page, CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein[J]. Nat Genet.1997,17(1):40-8.
[6]Geyer, HL, Bressman, SB. The diagnosis of dystonia[J]. Lancet Neurol.2006, 5(9):780-90.
[7]杨静芳,李建宇,李勇杰,等.原发性肌张力障碍患者DYT1基因突变分析[J].中华医学杂志.2007,33)：2324-2327.
[8]Yang, JF, Wu, T, Li, JY, et al. DYT1 mutations in early onset primary torsion dystonia and Parkinson disease patients in Chinese populations[J]. Neurosci Lett. 2009,450(2):117-21.
[9]Zhang, SS, Fang, DF, Hu, XH, et al. Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China[J]. Eur J Neurol. 2010,17(6):846-51.
[10]Cheng, FB, Wan, XH, Feng, JC, et al. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011,18(3):497-503.
[11]Zirn, B, Grundmann, K, Huppke, P, et al. Novel TORI A mutation p.Arg288Gln in early-onset dystonia (DYT1) [J]. J Neurol Neurosurg Psychiatry.2008,79(12): 1327-30.
[12]Calakos, N, Patel, VD, Gottron, M, et al. Functional evidence implicating a novel TORI A mutation in idiopathic, late-onset focal dystonia[J]. J Med Genet.2010, 47(9):646-50.
[13]Kabakci, K, Hedrich, K, Leung, JC, et al. Mutations in DYT1:extension of the phenotypic and mutational spectrum[J]. Neurology.2004,62(3):395-400.
[14]Gambarin, M, Valente, EM, Liberini, P, et al. Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia[J]. Mov Disord.2006,21(10):1782-4.
[15]Torres, GE, Sweeney, AL, Beaulieu, JM, et al. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant[J]. Proc Natl Acad Sci U S A.2004, 101(44):15650-5.
[16]McCarthy, DM, Gioioso, V, Zhang, X, et al. Neurogenesis and neuronal migration in the forebrain of the TorsinA knockout mouse embryo[J]. Dev Neurosci.2012, 34(4):366-78.
[17]Vander, Heyden AB, Naismith, TV, Snapp, EL, et al. Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum[J]. EMBO J.2011,30(16):3217-31.
[18]Hewett, JW, Zeng, J, Niland, BP, et al. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics[J]. Neurobiol Dis.2006,22(1):98-111.
[19]Kamm, C, Boston, H, Hewett, J, et al. The early onset dystonia protein torsinA interacts with kinesin light chain 1[J]. J Biol Chem.2004,279(19):19882-92.
[20]Xiao, J, Gong, S, Zhao, Y, et al. Developmental expression of rat torsinA transcript and protein[J]. Brain Res Dev Brain Res.2004,152(1):47-60.
[21]Vasudevan, A, Breakefield, XO, Bhide, PG. Developmental patterns of torsinA and torsinB expression[J]. Brain Res.2006,1073-1074(:139-45.
[22]McLean, PJ, Kawamata, H, Shariff, S, et al. TorsinA and heat shock proteins act as molecular chaperones:suppression of alpha-synuclein aggregation[J]. J Neurochem.2002,83(4):846-54.
[23]Esapa, CT, Waite, A, Locke, M, et al. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane:modulation by ubiquitination and torsinA[J]. Hum Mol Genet. 2007,16(3):327-42.
[24]Konakova, M, Pulst, SM. Dystonia-associated forms of torsinA are deficient in ATPase activity[J]. J Mol Neurosci.2005,25(1):105-17.
[25]Goodchild, RE, Dauer, WT. The AAA+protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein[J]. J Cell Biol.2005,168(6): 855-62.
[26]Parker, N. Hereditary whispering dysphonia[J]. J Neurol Neurosurg Psychiatry. 1985,48(3):218-24.
[27]Hersheson, J, Mencacci, NE, Davis, M, et al. Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.LID-10.1002/ana.23832 [doi]. Ann Neurol.2012.
[28]Alexoudi, A, Schneider, SA. De Novo mutations in the beta-tubulin gene TUBB4: from DYT4 to leukoencephalopathy with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome) [J]. Mov Disord.2013,28(10): 1343.
[29]Segawa, M, Hosaka, A, Miyagawa, F, et al. Hereditary progressive dystonia with marked diurnal fluctuation[J]. Adv Neurol.1976,14(:215-33.
[30]Nygaard, TG, Trugman, JM, de Yebenes JG, et al. Dopa-responsive dystonia:the spectrum of clinical manifestations in a large North American family [J]. Neurology.1990,40(1):66-9.
[31]Nygaard, TG, Wilhelmsen, KC, Risch, NJ, et al. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q[J]. Nat Genet.1993,5(4): 386-91.
[32]Ichinose, H, Ohye, T, Takahashi, E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene[J]. Nat Genet.1994,8(3):236-42.
[33]Furukawa, Y. Genetics and biochemistry of dopa-responsive dystonia: significance of striatal tyrosine hydroxylase protein loss[J]. Adv Neurol.2003, 91(:401-10.
[34]Steinberger, D, Korinthenberg, R, Topka, H, et al. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group[J]. Neurology.2000,55(11):1735-7.
[35]Almasy, L, Bressman, SB, Raymond, D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families[J]. Ann Neurol.1997,42(4):670-3.
[36]Fuchs, T, Gavarini, S, Saunders-Pullman, R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia[J]. Nat Genet.2009,41(3): 286-8.
[37]Blanchard, A, Ea, V, Roubertie, A, et al. DYT6 dystonia:review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene[J]. Hum Mutat.2011,32(11):1213-24.
[38]王琳,万新华,成伏波,等.DYT6型肌张力障碍患者的临床表现和影像学特点[J].中华神经科杂志,2013,46(3)：148-152.
[39]Bressman, SB, Raymond, D, Fuchs, T, et al. Mutations in THAP1 (DYT6) in early-onset dystonia:a genetic screening study. Lancet Neurol.2009,8(5):441-6.
[40]Houlden, H, Schneider, SA, Paudel, R, et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia[J]. Neurology.2010,74(10):846-50.
[41]朱晨雁,杨晓明.THAP蛋白家族研究进展[J].军事医学科学院院刊.2006, 06):569-572.
[42]Sengel, C, Gavarini, S, Sharma, N, et al. Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain[J]. J Neurochem. 2011,118(6):1087-100.
[43]Valente, EM, Spacey, SD, Wali, GM, et al. A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16ql3-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16[J]. Brain.2000,123 (Pt 10)(:2040-5.
[44]Chen, WJ, Lin, Y, Xiong, ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia[J]. Nat Genet. 2011,43(12):1252-5.
[45]Liu, Q, Qi, Z, Wan, XH, et al. Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression[J]. J Med Genet.2012, 49(2):79-82.
[46]Wang, JL, Cao, L, Li, XH, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias[J]. Brain.2011,134(Pt 12):3493-3501.
[47]Zimprich, A, Grabowski, M, Asmus, F, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome[J]. Nat Genet.2001, 29(1):66-9.
[48]Roze, E, Apartis, E, Clot, F, et al. Myoclonus-dystonia:clinical and electrophysiologic pattern related to SGCE mutations[J]. Neurology.2008,70(13): 1010-6.
[49]Tezenas, du Montcel S, Clot, F, Vidailhet, M, et al. Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes[J]. J Med Genet. 2006,43(5):394-400.
[50]Han, F, Lang, AE, Racacho, L, et al. Mutations in the epsilon-sarcoglycan gene found to be uncommon in seven myoclonus-dystonia families[J]. Neurology. 2003,61(2):244-6.
[51]Xiao, J, LeDoux, MS. Cloning, developmental regulation and neural localization of rat epsilon-sarcoglycan[J]. Brain Res Mol Brain Res.2003,119(2):132-43.
[52]Ritz, K, van, Schaik BD, Jakobs, ME, et al. SGCE isoform characterization and expression in human brain:implications for myoclonus-dystonia pathogenesis[J]. Eur J Hum Genet.2011,19(4):438-44.
[53]Waite, A, Tinsley, CL, Locke, M, et al. The neurobiology of the dystrophin-associated glycoprotein complex[J]. Ann Med.2009,41(5):344-59.
[54]LeDoux, MS. The genetics of dystonias[J]. Adv Genet.2012,79(:35-85.
[55]Rodacker, V, Toustrup-Jensen, M, Vilsen, B. Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+interaction by distinct mechanisms [J]. J Biol Chem.2006,281(27):18539-48.
[56]Brashear, A, Dobyns, WB, de Carvalho Aguiar P, et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP 1 A3 gene[J]. Brain.2007,130(Pt 3):828-35.
[57]Xiao, J, Uitti, RJ, Zhao, Y, et al. Mutations in CIZ1 cause adult onset primary cervical dystonia[J]. Ann Neurol.2012,71(4):458-69.
[58]Ma, L, Chen, R, Wang, L, et al. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013,28(13):1899-901.
[59]Charlesworth, G, Plagnol, V, Holmstrom, KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012,91(6):1041-50.
[60]Kang, HJ, Kawasawa, YI, Cheng, F, et al. Spatio-temporal transcriptome of the human brain[J]. Nature.2011,478(7370):483-9.
[61]Johnson, MB, Kawasawa, YI, Mason, CE, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis [J]. Neuron.2009,62(4):494-509.
[62]Stamelou, M, Charlesworth, G, Cordivari, C, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations.LID-10.1002/mds.25802 [doi]. Mov Disord. 2014
[63]Zech, M, Gross, N, Jochim, A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014,29(1): 143-7.
[64]Fuchs, T, Saunders-Pullman, R, Masuho, I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013,45(1):88-92.
[65]Drinnan, SL, Hope, BT, Snutch, TP, et al. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991,2(1):66-70.
[66]Herve, D, Levi-Strauss, M, Marey-Semper, I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993,13(5):2237-48.
[67]Kull, B, Svenningsson, P, Fredholm, BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000, 58(4)：771-7.
[68]Herve,D,Le,Moine C,Corvo1,JC,et al.Galpha(olf)levels are regulated byreceptor usage and control dopamine and adenosine action in the striatum[J].JNeurosci.2001,21(12)：4390-9.
[69]Corvol,JC,Studler,JM,Schonn,JS,et al.Galpha(olf)is necessary for CouplingD1 and A2a receptors to adenylyl cyclase in the striatum[J].J Neurochem.2001,76(5)：1585-8.
[70]Vemula,SR,Puschmann,A,Xiao,J,et al.Role of Galpha(o1f) in familial andsporadic adult-onset primary dystonia[J].Hum Mol Genet.2013,22(12)：2510-9.
[71]Kumar,KR,Lohmann,K,Masuho,I,et al.Mutations in GNAL：A Novel Causeof Craniocervical Dystonia.LID-10.1001/jamaneuro1.2013.4677[doi].JAMANeurol.2014.
[72]Charlesworth,G,Bhatia,KP,Wood,NW. No pathogenic GNAL mutations in 192sporadic and familial cases of cervical dystonia[J].Mov Disord.2014,29(1)：154-5.
[73]Fuchs,T,Saunders-Pullman,R,Masuho,I,et al.Mutations in GNAL causeprimary torsion dystonia[J].Nat Genet.2013,45(1)：88-92.
[74]Kaur,A.Rare autosomal dominant mutations in GNAL are associated withprimary torsion dystonia[J].Clin Genet.2013,84(3)：211-2.
[75]Miao,J,Wan,XH,Sun,Y, et al.Mutation screening of GNAL gene in patientswith primary dystonia from Northeast China[J].Parkinsonism Relat Disord.2013,19(10)：910-2.
[76]Zech,M,Gross,N,Jochim,A,et al.Rare sequence variants in AN03 and GNALin a primary torsion dystonia series and controls[J].Mov Disord.2014,29(1)：143-7.
[77]Dufke,C,Sturm,M,Schroeder,C,et al.Screening of mutations in GNAL insporadic dystonia patients.LID-10.1002/mds.25794[doi].Mov Disord.2014
[78]Saunders-Pullman,R,Fuchs,T,San,Luciano M,et al.Heterogeneity in primarydystonia：Lessons from THAP 1,GNAL,and TOR1 A in Amish-Mennonites.LID-10.1002/mds.25818[doi].Mov Disord.2014.
[2]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008.41(8)：570-573.
[3]汤晓芙,万新华,黄光.A型肉毒毒素治疗局限性肌张力障碍和肌肉痉挛[J].中华神经科杂志.1999.32(3)：135.
[4]Muller U, Steinberger D, Nemeth AH. Clinical and molecular genetics of primary dystonias. Neurogenetics[J].1998.1(3):165-77.
[5]Nemeth AH. The genetics of primary dystonias and related disorders[J]. Brain. 2002.125(Pt 4):695-721.
[6]LeDoux MS. The genetics of dystonias[J]. Adv Genet.2012.79:35-85.
[7]Defazio G, Abbruzzese G, Girlanda P, et al. Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia[J]. J Neurol.2012.259(11): 2414-8.
[8]Fletcher NA. The genetics of idiopathic torsion dystonia[J]. J Med Genet.1990. 27(7):409-12.
[9]Muller U, Kupke KG. The genetics of primary torsion dystonia[J]. Hum Genet. 1990.84(2):107-15.
[10]de Carvalho Aguiar PM, Ozelius LJ. Classification and genetics of dystonia[J]. Lancet Neurol.2002.1(5):316-25.
[11]Defazio G, Abbruzzese G, Livrea P, Berardelli A. Epidemiology of primary dystonia[J]. Lancet Neurol.2004.3(11):673-8.
[12]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013.45(1):88-92.
[13]Vemula SR, Puschmann A, Xiao J, et al. Role of Galpha(olf) in familial and sporadic adult-onset primary dystonia[J]. Hum Mol Genet.2013.22(12):2510-9.
[14]Herve D, Levi-Strauss M, Marey-Semper I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993.13(5):2237-48.
[15]Drinnan SL, Hope BT, Snutch TP, Vincent SR. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991.2(1):66-70.
[16]Kull B, Svenningsson P, Fredholm BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000. 58(4):771-7.
[17]Herve D, Le MC, Corvol JC, et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum[J]. J Neurosci. 2001.21(12):4390-9.
[18]Corvol JC, Studler JM, Schonn JS, Girault JA, Herve D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum[J]. J Neurochem.2001.76(5):1585-8.
[19]Miao J, Wan XH, Sun Y, Feng JC, Cheng FB. Mutation screening of GNAL gene in patients with primary dystonia from Northeast China[J]. Parkinsonism Relat Disord.2013.19(10):910-2.
[20]Kumar KR, Lohmann K, Masuho I, et al. Mutations in GNAL:A Novel Cause of Craniocervical Dystonia.LID-10.1001/jamaneurol.2013.4677 [doi]. JAMA Neurol.2014.
[21]Fahn S, Bressman SB, Marsden CD. Classification of dystonia[J]. Adv Neurol. 1998.78:1-10.
[22]Dufke C, Sturm M, Schroeder C, et al. Screening of mutations in GNAL in sporadic dystonia patients.LID-10.1002/mds.25794 [doi]. Mov Disord.2014.
[23]Saunders-Pullman R, Fuchs T, San LM, et al. Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.LID-10.1002/mds.25818 [doi]. Mov Disord.2014.
[24]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014.29(1): 143-7.
[25]Charlesworth G, Bhatia KP, Wood NW. No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia[J]. Mov Disord.2014.29(1): 154-5.
[26]Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G. Sporadic focal dystonia in northwest Germany:molecular basis on chromosome 18p[J]. Ann Neurol.1997.42(1):111-4.
[27]Awaad Y, Munoz S, Nigro M. Progressive dystonia in a child with chromosome 18p deletion, treated with intrathecal baclofen[J]. J Child Neurol.1999.14(2): 75-7.
[28]Bhidayasiri R, Jen JC, Baloh RW. Three brothers with a very-late-onset writer's cramp[J]. Mov Disord.2005.20(10):1375-7.
[29]Graziadio C, Rosa RF, Zen PR, Pinto LL, Barea LM, Paskulin GA. Dystonia, autoimmune disease and cerebral white matter abnormalities in a patient with 18p deletion[J]. Arq Neuropsiquiatr.2009.67(3A):689-91.
[30]Kowarik MC, Langer S, Keri C, Hemmer B, Oexle K, Winkelmann J. Myoclonus-dystonia in 18p deletion syndrome[J]. Mov Disord.2011.26(3): 560-1.
[31]Nasir J, Frima N, Pickard B, Malloy MP, Zhan L, Grunewald R. Unbalanced whole arm translocation resulting in loss of 18p in dystoni[J]a. Mov Disord.2006. 21(6):859-63.
[32]Postma AG, Verschuuren-Bemelmans CC, Kok K, van Laar T. Characteristics of dystonia in the 18p deletion syndrome, including a new case[J]. Clin Neurol Neurosurg.2009.111(10):880-2.
[33]Tezzon F, Zanoni T, Passarin MG, Ferrari G. Dystonia in a patient with deletion of 18p[J]. Ital J Neurol Sci.1998.19(2):90-3.
[34]Leube B, Rudnicki D, Ratzlaff T, Kessler KR, Benecke R, Auburger G. Idiopathic torsion dystonia:assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distributionfJ]. Hum Mol Genet.1996.5(10):1673-7.
[35]Klein C, Ozelius LJ, Hagenah J, Breakefield XO, Risch NJ, Vieregge P. Search for a founder mutation in idiopathic focal dystonia from Northern Germany [J]. Am J Hum Genet.1998.63(6):1777-82.
[36]Regnauld KL, Leteurtre E, Gutkind SJ, Gespach CP, Emami S. Activation of adenylyl cyclases, regulation of insulin status, and cell survival by G(alpha)olf in pancreatic beta-cells[J]. Am J Physiol Regul Integr Comp Physiol.2002. 282(3):R870-80.
[37]Wackym PA, Cioffi JA, Erbe CB, Popper P. G-protein Golfalpha (GNAL) is expressed in the vestibular end organs and primary afferent neurons of Rattus norvegicus[J]. J Vestib Res.2005.15(1):11-5.
[38]Belluscio L, Gold GH, Nemes A, Axel R. Mice deficient in G(olf) are anosmic[J]. Neuron.1998.20(1):69-81.
[39]Ghadami M, Majidzadeh-A K, Morovvati S, et al. Isolated congenital anosmia with morphologically normal olfactory bulb in two Iranian families:a new clinical entity[J]. Am J Med Genet A.2004.127A(3):307-9.
[40]Wang XZ, Zhong N. Clinical and genetic features of DYT1 and DYT5[J]. Beijing Da Xue Xue Bao.2006.38(1):107-9.
[41]Naiya T, Biswas A, Neogi R, et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients[J]. Acta Neurol Scand.2006. 114(3):210-5.
[42]Zhang SS, Fang DF, Hu XH, et al. Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China[J]. Eur J Neurol.2010.17(6): 846-51.
[43]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[44]Akbari MT, Zand Z, Shahidi GA, Hamid M. Clinical features, DYT1 mutation screening and genotype-phenotype correlation in patients with dystonia from Iran[J]. Med Princ Pract.2012.21(5):462-6.
[45]王琳,万新华,成伏波,杨英麦,马凌燕,崔丽英.DYT6型肌张力障碍患者的临床表现和影像学特点[J].中华神经科杂志.2013.46(3)：148-152.
[46]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[47]Miyamoto R, Koizumi H, Morino H, et al. DYT6 in Japan-genetic screening and clinical characteristics of the patients[J]. Mov Disord.2014.29(2):278-80.
[1]Jankovic J, Leder S, Warner D, et al. Cervical dystonia:clinical findings and associated movement disorders[J]. Neurology,1991,41(7):1088-91.
[2]Nutt JG, Muenter MD, Aronson A, et al. Epidemiology of focal and generalized dystonia in Rochester, Minnesota[J]. Mov Disord,1988,3(3):188-94.
[3]A prevalence study of primary dystonia in eight European countries[J]. J Neurol, 2000,247(10):787-92.
[4]Duffey PO, Butler AG, Hawthorne MR, et al. The epidemiology of the primary dystonias in the north of England[J]. Adv Neurol,1998,78:121-5.
[5]Velickovic M, Benabou R, Brin MF. Cervical dystonia pathophysiology and treatment options[J]. Drugs,2001,61(13):1921-43.
[6]Jahanshahi M, Marion MH, Marsden CD. Natural history of adult-onset idiopathic torticollis[J]. Arch Neurol,1990,47(5):548-52.
[7]Jahanshahi M. Factors that ameliorate or aggravate spasmodic torticollis[J]. J Neurol Neurosurg Psychiatry,2000,68(2):227-9.
[8]Poisson A, Krack P, Thobois S, et al. History of the'geste antagoniste'sign in cervical dystonia[J]. J Neurol,2012.
[9]Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence variants in primary dystonia[J]. Neurology.2010.74(3):229-38.
[10]Muller U. The monogenic primary dystonias[J]. Brain,2009,132(Pt 8):2005-25.
[11]Petrucci S, Valente EM. Genetic issues in the diagnosis of dystonias. Front Neurol. 2013.4:34.
[12]Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families[J]. Ann Neurol,1997,42(4):670-3.
[13]Cheng FB, Wan XH, Feng JC, et al. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol,2011,18(3):497-503.
[14]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China [J]. Eur J Neurol.2011. 18(3):497-503.
[15]Leube B, Hendgen T, Kessler KR, et al. Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe[J]. Am J Med Genet, 1997,74(5):529-32.
[16]Xiao J, Uitti RJ, Zhao Y, et al. Mutations in CIZ1 cause adult onset primary cervical dystonia[J]. Ann Neurol,2012,71(4):458-69.
[17]Charlesworth G, Plagnol V, Holmstrom KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012.91(6):1041-50.
[18]Kang HJ, Kawasawa YI, Cheng F, et al. Spatio-temporal transcriptome of the human brain[J]. Nature.2011.478(7370):483-9.
[19]Johnson MB, Kawasawa YI, Mason CE, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis[J]. Neuron.2009.62(4):494-509.
[20]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013.45(1):88-92.
[21]Ma L, Chen R, Wang L, Yang Y, Wan X. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013.28(13): 1899-901.
[22]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014.29(1): 143-7.
[23]Stamelou M, Charlesworth G, Cordivari C, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations.LID-10.1002/mds.25802 [doi]. Mov Disord. 2014.
[24]Hopfner F, Bungeroth M, Pendziwiat M, et al. Rare variants in ANO3 are not a susceptibility factor in essential tremor[J]. Parkinsonism Relat Disord.2014. 20(1):134-5.
[25]Herve D, Levi-Strauss M, Marey-Semper I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993.13(5):2237-48.
[26]Drinnan SL, Hope BT, Snutch TP, Vincent SR. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991.2(1):66-70.
[27]Kull B, Svenningsson P, Fredholm BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000. 58(4):771-7.
[28]Herve D, Le MC, Corvol JC, et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum[J]. J Neurosci. 2001.21(12):4390-9.
[29]Corvol JC, Studler JM, Schonn JS, Girault JA, Herve D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum[J]. J Neurochem.2001.76(5):1585-8.
[30]Vemula SR, Puschmann A, Xiao J, et al. Role of Galpha(olf) in familial and sporadic adult-onset primary dystonia[J]. Hum Mol Genet.2013.22(12):2510-9.
[31]Charlesworth G, Bhatia KP, Wood NW. No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia[J]. Mov Disord.2014.29(1): 154-5.
[1]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008.41(8)：570-573.
[2]Klein C, Ozelius LJ. Dystonia:clinical features, genetics, and treatment[J]. Curr Opin Neurol.2002.15(4):491-7.
[3]Defazio G, Abbruzzese G, Girlanda P, et al. Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia[J]. J Neurol.2012.259(11): 2414-8.
[4]Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011. 18(3):497-503.
[5]Ma L, Chen R, Wang L, Yang Y, Wan X. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013.28(13): 1899-901.
[6]Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls [J]. Mov Disord.2014.29(1): 143-7.
[7]Charlesworth G, Plagnol V, Holmstrom KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012.91(6):1041-50.
[8]Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystoni[J]a. Nat Genet.2013.45(1):88-92.
[9]Kaur A. Rare autosomal dominant mutations in GNAL are associated with primary torsion dystonia[J]. Clin Genet.2013.84(3):211-2.
[10]Miao J, Wan XH, Sun Y, Feng JC, Cheng FB. Mutation screening of GNAL gene in patients with primary dystonia from Northeast China[J]. Parkinsonism Relat Disord.2013.19(10):910-2.
[11]Saunders-Pullman R, Fuchs T, San LM, et al. Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.LID 10.1002/mds.25818 [doi]. Mov Disord.2014.
[12]Defazio G, Berardelli A, Hallett M. Do primary adult-onset focal dystonias share aetiological factors[J]. Brain.2007.130(Pt 5):1183-93.
[13]Sharma N, Franco RA Jr, Kuster JK, et al. Genetic evidence for an association of the TOR1A locus with segmental/focal dystoni[J]a. Mov Disord.2010.25(13): 2183-7.
[14]Chen Y, Song W, Yang J, et al. Association of the Va166Met polymorphism of the BDNF gene with primary cranial-cervical dystonia patients from South-west China[J]. Parkinsonism Relat Disord.2013.19(11):1043-5.
[15]Cramer SC, Sampat A, Haske-Palomino M, Nguyen S, Procaccio V, Hermanowicz N. Increased prevalence of val(66)met BDNF genotype among subjects with cervical dystonia[J]. Neurosci Lett.2010.468(1):42-5.
[16]Hallett M. Dystonia:a sensory and motor disorder of short latency inhibition[J]. Ann Neurol.2009.66(2):125-7.
[17]Kaji R. Basal ganglia as a sensory gating devise for motor control[J]. J Med Invest.2001.48(3-4):142-6.
[18]Quartarone A, Morgante F, Sant'angelo A, et al. Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia[J]. J Neurol Neurosurg Psychiatry.2008.79(9):985-90.
[19]Beck S, Richardson SP, Shamim EA, Dang N, Schubert M, Hallett M. Short intracortical and surround inhibition are selectively reduced during movement initiation in focal hand dystonia[J]. J Neurosci.2008.28(41):10363-9.
[20]Sohn YH, Hallett M. Disturbed surround inhibition in focal hand dystonia[J]. Ann Neurol.2004.56(4):595-9.
[21]Quartarone A, Sant'Angelo A, Battaglia F, et al. Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm[J]. J Neurosci.2006.26(2):716-21.
[22]Rothwell J. Transcranial magnetic stimulation as a method for investigating the plasticity of the brain in Parkinson's disease and dystonia[J]. Parkinsonism Relat Disord.2007.13 Suppl 3:S417-20.
[23]Tempel LW, Perlmutter JS. Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia[J]. Brain.1990.113 (Pt 3):691-707.
[24]Murase N, Shimadu H, Urushihara R, Kaji R. Abnormal sensorimotor integration in hand dystonia[J]. Suppl Clin Neurophysiol.2006.59:283-7.
[25]Cheeran B, Talelli P, Mori F, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS[J]. J Physiol.2008.586(Pt 23):5717-25.
[26]Lipsky RH, Marini AM. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity[J]. Ann NY Acad Sci.2007.1122:130-43.
[27]Cotman CW, Berchtold NC. Exercise:a behavioral intervention to enhance brain health and plasticity [J]. Trends Neurosci.2002.25(6):295-301.
[28]Lu B. BDNF and activity-dependent synaptic modulation[J]. Learn Mem.2003. 10(2):86-98.
[29]Klintsova AY, Dickson E, Yoshida R, Greenough WT. Altered expression of BDNF and its high-affinity receptor TrkB in response to complex motor learning and moderate exercise[J]. Brain Res.2004.1028(1):92-104.
[30]Egan MF, Kojima M, Callicott JH, et al. The BDNF va166met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function[J]. Cell.2003.112(2):257-69.
[31]Pezawas L, Verchinski BA, Mattay VS, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology[J]. J Neurosci.2004.24(45):10099-102.
[32]Hariri AR, Goldberg TE, Mattay VS, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance[J]. J Neurosci.2003.23(17):6690-4.
[33]Kleim JA, Chan S, Pringle E, et al. BDNF va166met polymorphism is associated with modified experience-dependent plasticity in human motor cortex[J]. Nat Neurosci.2006.9(6):735-7.
[34]Martino D, Muglia M, Abbruzzese G, et al. Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia[J]. Eur J Neurol.2009. 16(8):949-52.
[35]Groen JL, Ritz K, Velseboer DC, et al. Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia.LID-10.1002/mds.24922 [doi]. Mov Disord.2012.
[36]Svetel MV, Djuric G, Novakovic I, et al. A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia[J]. Acta Neurol Belg.2013.113(3):243-5.
[37]Fahn S, Bressman SB, Marsden CD. Classification of dystonia[J]. Adv Neurol. 1998.78:1-10.
[38]Lu B. BDNF and activity-dependent synaptic modulation[J]. Learn Mem.2003. 10(2):86-98.
[39]Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action[J]. Nat Rev Neurosci.2005.6(8):603-14.
[40]Hong CJ, Liou YJ, Tsai SJ. Effects of BDNF polymorphisms on brain function and behavior in health and disease[J]. Brain Res Bull.2011.86(5-6):287-97.
[41]Opal P, Tintner R, Jankovic J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia:from asymptomatic TOR1A gene carrier status to dystonic storm[J]. Mov Disord.2002.17(2):339-45.
[42]Karamohamed S, Latourelle JC, Racette BA, et al. BDNF genetic variants are associated with onset age of familial Parkinson disease:GenePD Study[J]. Neurology.2005.65(11):1823-5.
[43]Voineskos AN, Lerch JP, Felsky D, et al. The brain-derived neurotrophic factor Va166Met polymorphism and prediction of neural risk for Alzheimer disease[J]. Arch Gen Psychiatry.2011.68(2):198-206.
[44]Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study[J]. Am J Hum Genet.2002.71(3): 651-5.
[1]Klein, C, Ozelius, LJ. Dystonia:clinical features, genetics, and treatment[J]. Curr Opin Neurol.2002,15(4):491-7.
[2]中华医学会神经病学分会帕金森病及运动障碍学组.肌张力障碍诊断与治疗指南[J].中华神经科杂志.2008,41(8)：570-573.
[3]汤晓芙,万新华,黄光.A型肉毒毒素治疗局限性肌张力障碍和肌肉痉挛[J].中华神经科杂志.1999,32(3)：135.
[4]Muller, U. The monogenic primary dystonias[J]. Brain.2009,132(Pt 8):2005-25.
[5]Ozelius, LJ, Hewett, JW, Page, CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein[J]. Nat Genet.1997,17(1):40-8.
[6]Geyer, HL, Bressman, SB. The diagnosis of dystonia[J]. Lancet Neurol.2006, 5(9):780-90.
[7]杨静芳,李建宇,李勇杰,等.原发性肌张力障碍患者DYT1基因突变分析[J].中华医学杂志.2007,33)：2324-2327.
[8]Yang, JF, Wu, T, Li, JY, et al. DYT1 mutations in early onset primary torsion dystonia and Parkinson disease patients in Chinese populations[J]. Neurosci Lett. 2009,450(2):117-21.
[9]Zhang, SS, Fang, DF, Hu, XH, et al. Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China[J]. Eur J Neurol. 2010,17(6):846-51.
[10]Cheng, FB, Wan, XH, Feng, JC, et al. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China[J]. Eur J Neurol.2011,18(3):497-503.
[11]Zirn, B, Grundmann, K, Huppke, P, et al. Novel TORI A mutation p.Arg288Gln in early-onset dystonia (DYT1) [J]. J Neurol Neurosurg Psychiatry.2008,79(12): 1327-30.
[12]Calakos, N, Patel, VD, Gottron, M, et al. Functional evidence implicating a novel TORI A mutation in idiopathic, late-onset focal dystonia[J]. J Med Genet.2010, 47(9):646-50.
[13]Kabakci, K, Hedrich, K, Leung, JC, et al. Mutations in DYT1:extension of the phenotypic and mutational spectrum[J]. Neurology.2004,62(3):395-400.
[14]Gambarin, M, Valente, EM, Liberini, P, et al. Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia[J]. Mov Disord.2006,21(10):1782-4.
[15]Torres, GE, Sweeney, AL, Beaulieu, JM, et al. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant[J]. Proc Natl Acad Sci U S A.2004, 101(44):15650-5.
[16]McCarthy, DM, Gioioso, V, Zhang, X, et al. Neurogenesis and neuronal migration in the forebrain of the TorsinA knockout mouse embryo[J]. Dev Neurosci.2012, 34(4):366-78.
[17]Vander, Heyden AB, Naismith, TV, Snapp, EL, et al. Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum[J]. EMBO J.2011,30(16):3217-31.
[18]Hewett, JW, Zeng, J, Niland, BP, et al. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics[J]. Neurobiol Dis.2006,22(1):98-111.
[19]Kamm, C, Boston, H, Hewett, J, et al. The early onset dystonia protein torsinA interacts with kinesin light chain 1[J]. J Biol Chem.2004,279(19):19882-92.
[20]Xiao, J, Gong, S, Zhao, Y, et al. Developmental expression of rat torsinA transcript and protein[J]. Brain Res Dev Brain Res.2004,152(1):47-60.
[21]Vasudevan, A, Breakefield, XO, Bhide, PG. Developmental patterns of torsinA and torsinB expression[J]. Brain Res.2006,1073-1074(:139-45.
[22]McLean, PJ, Kawamata, H, Shariff, S, et al. TorsinA and heat shock proteins act as molecular chaperones:suppression of alpha-synuclein aggregation[J]. J Neurochem.2002,83(4):846-54.
[23]Esapa, CT, Waite, A, Locke, M, et al. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane:modulation by ubiquitination and torsinA[J]. Hum Mol Genet. 2007,16(3):327-42.
[24]Konakova, M, Pulst, SM. Dystonia-associated forms of torsinA are deficient in ATPase activity[J]. J Mol Neurosci.2005,25(1):105-17.
[25]Goodchild, RE, Dauer, WT. The AAA+protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein[J]. J Cell Biol.2005,168(6): 855-62.
[26]Parker, N. Hereditary whispering dysphonia[J]. J Neurol Neurosurg Psychiatry. 1985,48(3):218-24.
[27]Hersheson, J, Mencacci, NE, Davis, M, et al. Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.LID-10.1002/ana.23832 [doi]. Ann Neurol.2012.
[28]Alexoudi, A, Schneider, SA. De Novo mutations in the beta-tubulin gene TUBB4: from DYT4 to leukoencephalopathy with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome) [J]. Mov Disord.2013,28(10): 1343.
[29]Segawa, M, Hosaka, A, Miyagawa, F, et al. Hereditary progressive dystonia with marked diurnal fluctuation[J]. Adv Neurol.1976,14(:215-33.
[30]Nygaard, TG, Trugman, JM, de Yebenes JG, et al. Dopa-responsive dystonia:the spectrum of clinical manifestations in a large North American family [J]. Neurology.1990,40(1):66-9.
[31]Nygaard, TG, Wilhelmsen, KC, Risch, NJ, et al. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q[J]. Nat Genet.1993,5(4): 386-91.
[32]Ichinose, H, Ohye, T, Takahashi, E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene[J]. Nat Genet.1994,8(3):236-42.
[33]Furukawa, Y. Genetics and biochemistry of dopa-responsive dystonia: significance of striatal tyrosine hydroxylase protein loss[J]. Adv Neurol.2003, 91(:401-10.
[34]Steinberger, D, Korinthenberg, R, Topka, H, et al. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group[J]. Neurology.2000,55(11):1735-7.
[35]Almasy, L, Bressman, SB, Raymond, D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families[J]. Ann Neurol.1997,42(4):670-3.
[36]Fuchs, T, Gavarini, S, Saunders-Pullman, R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia[J]. Nat Genet.2009,41(3): 286-8.
[37]Blanchard, A, Ea, V, Roubertie, A, et al. DYT6 dystonia:review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene[J]. Hum Mutat.2011,32(11):1213-24.
[38]王琳,万新华,成伏波,等.DYT6型肌张力障碍患者的临床表现和影像学特点[J].中华神经科杂志,2013,46(3)：148-152.
[39]Bressman, SB, Raymond, D, Fuchs, T, et al. Mutations in THAP1 (DYT6) in early-onset dystonia:a genetic screening study. Lancet Neurol.2009,8(5):441-6.
[40]Houlden, H, Schneider, SA, Paudel, R, et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia[J]. Neurology.2010,74(10):846-50.
[41]朱晨雁,杨晓明.THAP蛋白家族研究进展[J].军事医学科学院院刊.2006, 06):569-572.
[42]Sengel, C, Gavarini, S, Sharma, N, et al. Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain[J]. J Neurochem. 2011,118(6):1087-100.
[43]Valente, EM, Spacey, SD, Wali, GM, et al. A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16ql3-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16[J]. Brain.2000,123 (Pt 10)(:2040-5.
[44]Chen, WJ, Lin, Y, Xiong, ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia[J]. Nat Genet. 2011,43(12):1252-5.
[45]Liu, Q, Qi, Z, Wan, XH, et al. Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression[J]. J Med Genet.2012, 49(2):79-82.
[46]Wang, JL, Cao, L, Li, XH, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias[J]. Brain.2011,134(Pt 12):3493-3501.
[47]Zimprich, A, Grabowski, M, Asmus, F, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome[J]. Nat Genet.2001, 29(1):66-9.
[48]Roze, E, Apartis, E, Clot, F, et al. Myoclonus-dystonia:clinical and electrophysiologic pattern related to SGCE mutations[J]. Neurology.2008,70(13): 1010-6.
[49]Tezenas, du Montcel S, Clot, F, Vidailhet, M, et al. Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes[J]. J Med Genet. 2006,43(5):394-400.
[50]Han, F, Lang, AE, Racacho, L, et al. Mutations in the epsilon-sarcoglycan gene found to be uncommon in seven myoclonus-dystonia families[J]. Neurology. 2003,61(2):244-6.
[51]Xiao, J, LeDoux, MS. Cloning, developmental regulation and neural localization of rat epsilon-sarcoglycan[J]. Brain Res Mol Brain Res.2003,119(2):132-43.
[52]Ritz, K, van, Schaik BD, Jakobs, ME, et al. SGCE isoform characterization and expression in human brain:implications for myoclonus-dystonia pathogenesis[J]. Eur J Hum Genet.2011,19(4):438-44.
[53]Waite, A, Tinsley, CL, Locke, M, et al. The neurobiology of the dystrophin-associated glycoprotein complex[J]. Ann Med.2009,41(5):344-59.
[54]LeDoux, MS. The genetics of dystonias[J]. Adv Genet.2012,79(:35-85.
[55]Rodacker, V, Toustrup-Jensen, M, Vilsen, B. Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+interaction by distinct mechanisms [J]. J Biol Chem.2006,281(27):18539-48.
[56]Brashear, A, Dobyns, WB, de Carvalho Aguiar P, et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP 1 A3 gene[J]. Brain.2007,130(Pt 3):828-35.
[57]Xiao, J, Uitti, RJ, Zhao, Y, et al. Mutations in CIZ1 cause adult onset primary cervical dystonia[J]. Ann Neurol.2012,71(4):458-69.
[58]Ma, L, Chen, R, Wang, L, et al. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families[J]. Mov Disord.2013,28(13):1899-901.
[59]Charlesworth, G, Plagnol, V, Holmstrom, KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia:ion channel implicated in pathogenesis[J]. Am J Hum Genet.2012,91(6):1041-50.
[60]Kang, HJ, Kawasawa, YI, Cheng, F, et al. Spatio-temporal transcriptome of the human brain[J]. Nature.2011,478(7370):483-9.
[61]Johnson, MB, Kawasawa, YI, Mason, CE, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis [J]. Neuron.2009,62(4):494-509.
[62]Stamelou, M, Charlesworth, G, Cordivari, C, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations.LID-10.1002/mds.25802 [doi]. Mov Disord. 2014
[63]Zech, M, Gross, N, Jochim, A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls[J]. Mov Disord.2014,29(1): 143-7.
[64]Fuchs, T, Saunders-Pullman, R, Masuho, I, et al. Mutations in GNAL cause primary torsion dystonia[J]. Nat Genet.2013,45(1):88-92.
[65]Drinnan, SL, Hope, BT, Snutch, TP, et al. G(olf) in the basal ganglia[J]. Mol Cell Neurosci.1991,2(1):66-70.
[66]Herve, D, Levi-Strauss, M, Marey-Semper, I, et al. G(olf) and Gs in rat basal ganglia:possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase[J]. J Neurosci.1993,13(5):2237-48.
[67]Kull, B, Svenningsson, P, Fredholm, BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum[J]. Mol Pharmacol.2000, 58(4)：771-7.
[68]Herve,D,Le,Moine C,Corvo1,JC,et al.Galpha(olf)levels are regulated byreceptor usage and control dopamine and adenosine action in the striatum[J].JNeurosci.2001,21(12)：4390-9.
[69]Corvol,JC,Studler,JM,Schonn,JS,et al.Galpha(olf)is necessary for CouplingD1 and A2a receptors to adenylyl cyclase in the striatum[J].J Neurochem.2001,76(5)：1585-8.
[70]Vemula,SR,Puschmann,A,Xiao,J,et al.Role of Galpha(o1f) in familial andsporadic adult-onset primary dystonia[J].Hum Mol Genet.2013,22(12)：2510-9.
[71]Kumar,KR,Lohmann,K,Masuho,I,et al.Mutations in GNAL：A Novel Causeof Craniocervical Dystonia.LID-10.1001/jamaneuro1.2013.4677[doi].JAMANeurol.2014.
[72]Charlesworth,G,Bhatia,KP,Wood,NW. No pathogenic GNAL mutations in 192sporadic and familial cases of cervical dystonia[J].Mov Disord.2014,29(1)：154-5.
[73]Fuchs,T,Saunders-Pullman,R,Masuho,I,et al.Mutations in GNAL causeprimary torsion dystonia[J].Nat Genet.2013,45(1)：88-92.
[74]Kaur,A.Rare autosomal dominant mutations in GNAL are associated withprimary torsion dystonia[J].Clin Genet.2013,84(3)：211-2.
[75]Miao,J,Wan,XH,Sun,Y, et al.Mutation screening of GNAL gene in patientswith primary dystonia from Northeast China[J].Parkinsonism Relat Disord.2013,19(10)：910-2.
[76]Zech,M,Gross,N,Jochim,A,et al.Rare sequence variants in AN03 and GNALin a primary torsion dystonia series and controls[J].Mov Disord.2014,29(1)：143-7.
[77]Dufke,C,Sturm,M,Schroeder,C,et al.Screening of mutations in GNAL insporadic dystonia patients.LID-10.1002/mds.25794[doi].Mov Disord.2014
[78]Saunders-Pullman,R,Fuchs,T,San,Luciano M,et al.Heterogeneity in primarydystonia：Lessons from THAP 1,GNAL,and TOR1 A in Amish-Mennonites.LID-10.1002/mds.25818[doi].Mov Disord.2014.