中国早发性帕金森病患者的parkin和PINK1基因突变分析及临床特征
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摘要
研究背景:
帕金森病(PD)是最常见的神经退行性疾病之一。在65岁以上的人群中帕金森病的患病率达到1%以上。在临床上主要表现为静止性震颤、强直、运动迟缓以及对左旋多巴治疗有明显疗效,特征性的病理改变主要是黑质致密部大量多巴胺神经元的丢失和残存多巴胺神经元内路易小体形成。到目前,帕金森病的确切病因仍未阐明,但是,越来越多的基因被认为对PD起致病作用,α-synuclein,UCH-L1,和LRRK2的突变被认为参与了家族性常染色体显性遗传性帕金森病的发病,而parkin,PINK1,DJ-1和ATP13A2被认为是早发型常染色体隐性遗传帕金森病的致病性基因。据我们所知,帕金森病通常被划分成早发型PD(early-onset PD,EOPD)和晚发型PD(late-onset PD,LOPD),家族性和散发性,以及常染色体显性遗传和隐性遗传。大多数文献把发病年龄小于50岁的帕金森病定为早发型。
在1997年,通过连锁分析Parkin基因被Matsumine等锁定在染色体6q25.2-q27。Parkin基因突变在EOPD中具有很高的检出率。在亚洲,韩国、中国以及台湾地区都对parkin基因有过研究报道。Chung EJ等采用基因定量分析的方法在94例EOPD中发现3例患者携带parkin基因的复杂杂合突变;Guo JF等采用直接测序和实时定量PCR的方法对29个中国家系的45例EOPD患者的DNA进行分析,发现14个家系中的25例患者携带不同类型的parkin基因突变,包括点突变、杂合突变、纯合突变以及复合型杂合突变;Wu RM等在41例EOPD中发现4例患者携带parkin基因的突变。
PINK1基因是在研究肿瘤抑制物PTEN的作用机制过程中被发现的。到目前,文献报道PINK1基因的外显子重排突变极其罕见,主要是点突变。因此,针对PINK1基因的突变分析,大多采用变性高效液相色谱技术(Denaturing High PerformanceLiquid Chromatography,DHPLC)和直接测序的方法。PINK1基因突变率在不同的族群中有所不同,基本在1%-9%,成为继parkin之后,EOPD的第二常见突变基因。
目前国内对EOPD患者的parkin和PINK1基因的突变分析报道仍很少见,且缺乏对基因突变和临床表型之间的相关分析。因此,对中国EOPD患者的parkin和PINK1基因的突变筛查以及相关临床特征的分析显的很有必要。
目的:
运用DHPLC和直接测序的方法分析研究中国EOPD患者parkin和PINK1基因点突变情况,以及运用实时定量PCR分析parkin基因外显子重排突变,并探讨PD患者基因型与临床表型之间关系。
方法:
按照以下标准在浙江大学医学院附属第二医院神经内科收集69例EOPD患者,(1)发病年龄小于50岁;(2)至少具备帕金森病四项特征性症状中两项(静止性震颤、运动迟缓、肌肉强直、姿势障碍);(3)对左旋多巴治疗有好的反应;(4)排除由其他神经系统疾病或药物或毒性物品引起的继发性帕金森病患者。首先,采用实时定量PCR的方法检测parkin基因12个外显子的重排突变;对没有重排突变或只有杂合重排突变的外显子再作DHPLC分析和直接测序排除parkin基因点突变;最后,对仍未查到突变或只有杂合突变的病例作DHPLC分析和直接测序筛查PINK1基因的点突变。
结果:
第一:应用荧光定量PCR方法发现19例PD患者具有parkin基因不同外显子的重排突变。其中,M630和M631患者为两姐妹都为3号、4号和7号外显子的杂合缺失;M5患者含有3号和4号外显子的纯合缺失;M6患者含有2号、6号外显子的杂合缺失;M10患者含有4号外显子纯合缺失;M30患者6号外显子杂合缺失和11号外显子杂合重复;另外,6例患者含有单一外显子的杂合缺失;7例患者含有单一外显子的杂合重复。
第二:应用DHPLC和直接测序的方法在一例患者的parkin基因上发现一新的呈杂合状态的单一碱基变异位点c.2T＞C(p.M1T),另外,在parkin和PINK1基因上发现多个SNPs。
第三:临床上,在含有纯合突变或复合杂合突变的患者中,其PD起病时常为双侧对称出现症状,如抖动、肌肉强直、运动迟缓。有突变(包括单一杂合突变)的患者起病年龄明显早于不含突变的患者。
结论:
第一:在本组患者中,parkin基因的突变率为28%,低于大多文献报道的50%,很可能是因为我们选的患者多是散发性的,而不是家族性PD。
第二:除了SNP外,本研究在PINK1基因上没有发现突变,这正是说明了PINK1基因的低突变率,而且在我国的PD患者中尤为低。
第三:有parkin基因突变的患者除了PD起病年龄明显早于无parkin基因突变的患者外,没有其他区别于无parkin基因突变患者的特异临床症状,所以从临床表现上无法去判断PD患者是否含有parkin或PINK1基因的突变。
Background:
Parkinson's disease(PD) is one of the most common neurodegenerative disorders, with a prevalence of more than 1%among persons older than 65 years of age.Clinical features of PD include resting tremor,rigidity,bradykinesia and a good response to levodopa;the main features in pathology are loss of dopaminergic neurons in substantia nigra pars compacta and emergence of Lewy bodies in surviving dopaminergic neurons. To date,the definite reason of PD is unknown,but more and more genes are regarded as PD-caused factors,mutations in genes of a-synuclein,UCH-L1,and LRRK2 are reported to be the causative genes for familial autosomal dominant PD,and mutations in genes of parkin,PINK1,D J-1,and ATP13A2 are reported to be the causative genes for autosomal recessive early-onset PD.To our knowledge,PD is usually divided into early-onset PD(EOPD) and late-onset PD(LOPD),or familial PD and sporadic PD,or autosomal dominant PD and autosomal recessive PD.Onset age of PD less than 50 years was definited as EOPD in most literatures.
In 1997,parkin gene was mapped to chromosome 6q25.2-q27 by Matsumine et al. by linkage analysis.The mutation frequency of parkin gene is very high among EOPD. Excepting Japan in Asia,China,Korea,and Taiwan of China also reported the research results of parkin gene in EOPD patients.Chung EJ et al.detected compound heterozygous mutations in 3 patients among 94 EOPD patients with gene dosage analysis;Guo et al.analyzed 45 EOPD patients in 29 families with direct sequencing and real-time quantitative PCR,and detected 25 parkin patients in 14 families with different mutation types,including point mutation,heterozygous mutation,homozygous mutation,and compound heterozygous mutation;Wu RM et al.detected 4 parkin mutation carriers in 41 EOPD patients.
PINK1 gene was found during the study of exploring the mechanism of tumor suppressor PTEN.To date,the mutation of PINK1 gene mainly is point mutation,the exon rearrangement is very rare.So when to detect mutation of PINK1,mostly researchers performed DHPLC(denaturing high performance liquid chromatography) and direct-sequencing.The mutation frequency of PINK1 was different in different groups,mostly between 1%and 9%,and became the second mutation gene of EOPD after parkin gene.
To date,study of detecting parkin and PINK1 mutation in EOPD patients is still very few in Zhejiang province in China,furthermore the correlation analysis between genotype and phenotype is lack.So the study of detecting parkin and PINK1 mutation in EOPD patients in Zhejiang province in China is necessary,and the correlation analysis between genotype and phenotype is very necessary.
Objective:
Analyzing point mutations of parkin and PINK1 genes in EOPD patients in Zhejiang province of China with Denaturing High Performance Liquid Chromatography (DHPLC) and direct-sequencing,and analyzing exon rearrangements of parkin gene with real time quantitative PCR,also we analyzed correlation between phenotype and genotype of PD patients.
Methods:
We selected 69 Chinese patients according to the following criteria:(1) age at onset＜50 years;(2) the presence of at least two signs of the four cardinal features (resting tremor,bradykinesia,rigidity and postural instability);(3) a good response to the treatment of levodopa;(4) excluding the patients with evidence of secondary parkinsonism caused by other neurologic diseases or known drugs or toxins.Firstly,we detected the rearrangement mutations of 12 exons in parkin gene with real time quantitative PCR in 69 patients;then detected point mutations with DHPLC and direct-sequencing in those patients who did not carry rearrangement mutations or only carry heterozygous rearrangements;lastly detected point mutations in 8 exons of PINIK1 gene in those patients who did not carry mutations or only carry heterozygous mutations.
Results:
First,by using real time quantitative PCR,we found that 19 cases carried different exon rearrangement mutations in parkin gene.M630 and M631 are sisters,both carried heterozygous deletions in exon 3,4,and 7 ofparkin;M5 carried homozygous deletions in exon 3 and 4 ofparkin;M6 carried heterozygous deletions in exon 2 and 6 ofparkin; M10 carried homozygous deletion in exon 4 of parkin;M30 carried heterozygous deletion in exon 6 and heterozygous duplication in exon 11 of parkin.In addition to these,6 cases carried heterozygous deletion in different single exon ofparkin;and 7 cases carried heterozygous duplication in different single exon ofparkin.
Second,we found a new heterozygous point mutation c.2T＞C(p.M1T) in parkin gene in one patient by using DHPLC and direct-sequencing.In addition,several SNPs were found in parkin and PINK1 genes.
Third,patients with homozygous or compound heterozygous mutations in the parkin gene mostly had a history of symmetrical onset,such as resting tremor,rigidity and bradykinesia;and the onset age of patients with mutation in parkin is earlier significantly than that of patients without mutation in parkin.
Conclusion:
First,the mutational frequency ofparkin is 28%in this study,which is lower than 50%in many other studies.The reason for this probably is:most patients are sporadic PD,not familial PD in our study.
Second,excepting SNP,no mutation was found in PINK1 gene,this result indicates that the mutational frequency of PINK1 is very low,especially in Chinese PD patients.
Third,the onset age of PD patients with parkin mutation is significantly earlier than those without parkin mutation,in addition to this,there is no other special clinical feature,so we can not judge whether a patient has mutation in parkin or PINK1 gene according to the clinical symptom.
帕金森病(PD)是最常见的神经退行性疾病之一。在65岁以上的人群中帕金森病的患病率达到1%以上。在临床上主要表现为静止性震颤、强直、运动迟缓以及对左旋多巴治疗有明显疗效,特征性的病理改变主要是黑质致密部大量多巴胺神经元的丢失和残存多巴胺神经元内路易小体形成。到目前,帕金森病的确切病因仍未阐明,但是,越来越多的基因被认为对PD起致病作用,α-synuclein,UCH-L1,和LRRK2的突变被认为参与了家族性常染色体显性遗传性帕金森病的发病,而parkin,PINK1,DJ-1和ATP13A2被认为是早发型常染色体隐性遗传帕金森病的致病性基因。据我们所知,帕金森病通常被划分成早发型PD(early-onset PD,EOPD)和晚发型PD(late-onset PD,LOPD),家族性和散发性,以及常染色体显性遗传和隐性遗传。大多数文献把发病年龄小于50岁的帕金森病定为早发型。
在1997年,通过连锁分析Parkin基因被Matsumine等锁定在染色体6q25.2-q27。Parkin基因突变在EOPD中具有很高的检出率。在亚洲,韩国、中国以及台湾地区都对parkin基因有过研究报道。Chung EJ等采用基因定量分析的方法在94例EOPD中发现3例患者携带parkin基因的复杂杂合突变;Guo JF等采用直接测序和实时定量PCR的方法对29个中国家系的45例EOPD患者的DNA进行分析,发现14个家系中的25例患者携带不同类型的parkin基因突变,包括点突变、杂合突变、纯合突变以及复合型杂合突变;Wu RM等在41例EOPD中发现4例患者携带parkin基因的突变。
PINK1基因是在研究肿瘤抑制物PTEN的作用机制过程中被发现的。到目前,文献报道PINK1基因的外显子重排突变极其罕见,主要是点突变。因此,针对PINK1基因的突变分析,大多采用变性高效液相色谱技术(Denaturing High PerformanceLiquid Chromatography,DHPLC)和直接测序的方法。PINK1基因突变率在不同的族群中有所不同,基本在1%-9%,成为继parkin之后,EOPD的第二常见突变基因。
目前国内对EOPD患者的parkin和PINK1基因的突变分析报道仍很少见,且缺乏对基因突变和临床表型之间的相关分析。因此,对中国EOPD患者的parkin和PINK1基因的突变筛查以及相关临床特征的分析显的很有必要。
目的:
运用DHPLC和直接测序的方法分析研究中国EOPD患者parkin和PINK1基因点突变情况,以及运用实时定量PCR分析parkin基因外显子重排突变,并探讨PD患者基因型与临床表型之间关系。
方法:
按照以下标准在浙江大学医学院附属第二医院神经内科收集69例EOPD患者,(1)发病年龄小于50岁;(2)至少具备帕金森病四项特征性症状中两项(静止性震颤、运动迟缓、肌肉强直、姿势障碍);(3)对左旋多巴治疗有好的反应;(4)排除由其他神经系统疾病或药物或毒性物品引起的继发性帕金森病患者。首先,采用实时定量PCR的方法检测parkin基因12个外显子的重排突变;对没有重排突变或只有杂合重排突变的外显子再作DHPLC分析和直接测序排除parkin基因点突变;最后,对仍未查到突变或只有杂合突变的病例作DHPLC分析和直接测序筛查PINK1基因的点突变。
结果:
第一:应用荧光定量PCR方法发现19例PD患者具有parkin基因不同外显子的重排突变。其中,M630和M631患者为两姐妹都为3号、4号和7号外显子的杂合缺失;M5患者含有3号和4号外显子的纯合缺失;M6患者含有2号、6号外显子的杂合缺失;M10患者含有4号外显子纯合缺失;M30患者6号外显子杂合缺失和11号外显子杂合重复;另外,6例患者含有单一外显子的杂合缺失;7例患者含有单一外显子的杂合重复。
第二:应用DHPLC和直接测序的方法在一例患者的parkin基因上发现一新的呈杂合状态的单一碱基变异位点c.2T＞C(p.M1T),另外,在parkin和PINK1基因上发现多个SNPs。
第三:临床上,在含有纯合突变或复合杂合突变的患者中,其PD起病时常为双侧对称出现症状,如抖动、肌肉强直、运动迟缓。有突变(包括单一杂合突变)的患者起病年龄明显早于不含突变的患者。
结论:
第一:在本组患者中,parkin基因的突变率为28%,低于大多文献报道的50%,很可能是因为我们选的患者多是散发性的,而不是家族性PD。
第二:除了SNP外,本研究在PINK1基因上没有发现突变,这正是说明了PINK1基因的低突变率,而且在我国的PD患者中尤为低。
第三:有parkin基因突变的患者除了PD起病年龄明显早于无parkin基因突变的患者外,没有其他区别于无parkin基因突变患者的特异临床症状,所以从临床表现上无法去判断PD患者是否含有parkin或PINK1基因的突变。
Background:
Parkinson's disease(PD) is one of the most common neurodegenerative disorders, with a prevalence of more than 1%among persons older than 65 years of age.Clinical features of PD include resting tremor,rigidity,bradykinesia and a good response to levodopa;the main features in pathology are loss of dopaminergic neurons in substantia nigra pars compacta and emergence of Lewy bodies in surviving dopaminergic neurons. To date,the definite reason of PD is unknown,but more and more genes are regarded as PD-caused factors,mutations in genes of a-synuclein,UCH-L1,and LRRK2 are reported to be the causative genes for familial autosomal dominant PD,and mutations in genes of parkin,PINK1,D J-1,and ATP13A2 are reported to be the causative genes for autosomal recessive early-onset PD.To our knowledge,PD is usually divided into early-onset PD(EOPD) and late-onset PD(LOPD),or familial PD and sporadic PD,or autosomal dominant PD and autosomal recessive PD.Onset age of PD less than 50 years was definited as EOPD in most literatures.
In 1997,parkin gene was mapped to chromosome 6q25.2-q27 by Matsumine et al. by linkage analysis.The mutation frequency of parkin gene is very high among EOPD. Excepting Japan in Asia,China,Korea,and Taiwan of China also reported the research results of parkin gene in EOPD patients.Chung EJ et al.detected compound heterozygous mutations in 3 patients among 94 EOPD patients with gene dosage analysis;Guo et al.analyzed 45 EOPD patients in 29 families with direct sequencing and real-time quantitative PCR,and detected 25 parkin patients in 14 families with different mutation types,including point mutation,heterozygous mutation,homozygous mutation,and compound heterozygous mutation;Wu RM et al.detected 4 parkin mutation carriers in 41 EOPD patients.
PINK1 gene was found during the study of exploring the mechanism of tumor suppressor PTEN.To date,the mutation of PINK1 gene mainly is point mutation,the exon rearrangement is very rare.So when to detect mutation of PINK1,mostly researchers performed DHPLC(denaturing high performance liquid chromatography) and direct-sequencing.The mutation frequency of PINK1 was different in different groups,mostly between 1%and 9%,and became the second mutation gene of EOPD after parkin gene.
To date,study of detecting parkin and PINK1 mutation in EOPD patients is still very few in Zhejiang province in China,furthermore the correlation analysis between genotype and phenotype is lack.So the study of detecting parkin and PINK1 mutation in EOPD patients in Zhejiang province in China is necessary,and the correlation analysis between genotype and phenotype is very necessary.
Objective:
Analyzing point mutations of parkin and PINK1 genes in EOPD patients in Zhejiang province of China with Denaturing High Performance Liquid Chromatography (DHPLC) and direct-sequencing,and analyzing exon rearrangements of parkin gene with real time quantitative PCR,also we analyzed correlation between phenotype and genotype of PD patients.
Methods:
We selected 69 Chinese patients according to the following criteria:(1) age at onset＜50 years;(2) the presence of at least two signs of the four cardinal features (resting tremor,bradykinesia,rigidity and postural instability);(3) a good response to the treatment of levodopa;(4) excluding the patients with evidence of secondary parkinsonism caused by other neurologic diseases or known drugs or toxins.Firstly,we detected the rearrangement mutations of 12 exons in parkin gene with real time quantitative PCR in 69 patients;then detected point mutations with DHPLC and direct-sequencing in those patients who did not carry rearrangement mutations or only carry heterozygous rearrangements;lastly detected point mutations in 8 exons of PINIK1 gene in those patients who did not carry mutations or only carry heterozygous mutations.
Results:
First,by using real time quantitative PCR,we found that 19 cases carried different exon rearrangement mutations in parkin gene.M630 and M631 are sisters,both carried heterozygous deletions in exon 3,4,and 7 ofparkin;M5 carried homozygous deletions in exon 3 and 4 ofparkin;M6 carried heterozygous deletions in exon 2 and 6 ofparkin; M10 carried homozygous deletion in exon 4 of parkin;M30 carried heterozygous deletion in exon 6 and heterozygous duplication in exon 11 of parkin.In addition to these,6 cases carried heterozygous deletion in different single exon ofparkin;and 7 cases carried heterozygous duplication in different single exon ofparkin.
Second,we found a new heterozygous point mutation c.2T＞C(p.M1T) in parkin gene in one patient by using DHPLC and direct-sequencing.In addition,several SNPs were found in parkin and PINK1 genes.
Third,patients with homozygous or compound heterozygous mutations in the parkin gene mostly had a history of symmetrical onset,such as resting tremor,rigidity and bradykinesia;and the onset age of patients with mutation in parkin is earlier significantly than that of patients without mutation in parkin.
Conclusion:
First,the mutational frequency ofparkin is 28%in this study,which is lower than 50%in many other studies.The reason for this probably is:most patients are sporadic PD,not familial PD in our study.
Second,excepting SNP,no mutation was found in PINK1 gene,this result indicates that the mutational frequency of PINK1 is very low,especially in Chinese PD patients.
Third,the onset age of PD patients with parkin mutation is significantly earlier than those without parkin mutation,in addition to this,there is no other special clinical feature,so we can not judge whether a patient has mutation in parkin or PINK1 gene according to the clinical symptom.
引文
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[18] Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet, 2005; 14:2099-2111.
[19] Paisan-Ruiz C, et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of Neurology, 2009; 65:19-23.
[20] Di Fonzo A, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology, 2009; 72:240-245.
[21] Gasser T. Mendelian forms of Parkinson's disease. Biochim Biophys Acta, published online 2009, doi: 10.1016/j.bbadis.2008.12.007.
[22] Hattori N, Kitada T, Matsumine H, et al. Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals. Ann Neurol, 1998; 44:935-41.
[23] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 1998; 392:605-608.
[24] Lucking CB, Bonifati V, Periquet M, et al. Pseudo- dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology, 2001; 57: 924-927.
[25] Foroud T, Uniacke SK, Liu L, et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology, 2003; 60:796 - 801.
[26] Pankratz N, Foroud T. Genetics of Parkinson disease. The American Society for Experimental Neuro Therapeutics, 2004; 1:235-242.
[27] Biskup S, Gerlach M, Kupsch A, et al. Genes associated with Parkinson syndrome. J Neurol, 2008; 255[suppl5]:8-17.
[28] Hattori N, Matsumine H, Asakawa S, et al. Point mutations (Thr240Arg and Ala311Stop) in the parkin gene. Biochem Biophys Res Commun, 1998; 249:754-8. [Erratum, Biochem Biophys Res Commun 1998; 251:666].
[29] Livak KJ, Schmittgen TD. Analysisof relative gene expression data using real-time quantitative PCR and the 2~(-KKCT) method. Methods, 2001; 25:402-408.
[30] Abou-Sleiman PM, Muqit MM, Wood NM. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci, 2006; 7:207-219.
[31] Mizuno Y, Hattori N, Kubo S, et al. Progress in the pathogenesis and genetics of Parkinson's disease. Phil Trans R Soc B, 2008; 363:2215-2227.
[32] Li Y, et al. Clinicogenetic study of PINKl mutations in autosomal recessive early-onset Parkinsonism. Neurology, 2005; 64:1955-1957.
[33] Guo JF, Xiao B, Liao B, et al. Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese patients with autosomal recessive early-onset parkinsonism. Mov Disord, 2008; 23:2074-2093.
[34] Lee MJ, Mata IF, Lin CH, et al. Genotype-phenotype correlates in Taiwanese patients with early-onset recessive parkinsonism. Mov Disord, 2009; 24:104-108.
[35] Tan EK, Yew K, Chua E, et al. PINKl mutations in sporadic early-onset Parkinson's disease. Mov Disord, 2006; 21:789-793.
[36] Silvestri L, Caputo V, Bellacchio E, et al. Mitochondrial import and enzymatic activity of PINKl mutants associated to recessive parkinsonism. Hum Mol Genet, 2005; 14:3477-3492.
[37] Sim CH, Lio DS, Mok SS, et al. C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet, 2006; 15:3251-3262.
[38] Petit A, Kawarai T, Paitel E,et al.Wild-type PINKl prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem, 2006; 280:34025-34032.
[39] Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin. Proc Natl Acad Sci USA, 2006; 103:10793-10798.
[40]Clark IE,Dodson MW,Jiang C,et al.Drosophila pinkl is required for mitochondrial function and interacts genetically with parkin.Nature,2006;441:1162-1166.
[41]Park J,Lee SB,Lee S,et al.Mitochondrial dysfunction in Drosophila PINK1mutants is complemented by parkin.Nature,2006;441:1157-1161.
[42]Tang B,Xiong H,Sun P,et al.Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.Hum Mol Genet,2006;15:1816-1825.
[43]Wang T,Liang Z,Sun S,et al.A novel point mutation in parkin gene was identified in an early-onset case of Parkinson's disease.Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2003;20:111-113.
[44]Yin Chan DK,Mok V,Ng PW,et al.PARK2 mutations and clinical features in a Chinese population with early-onset Parkinson's disease.J Neural Transm,2008;115:715-719.
[45]Shadrina MI,Semenova EV,Slominsky PA,et al.Effective quantitative real-time polymerase chain reaction analysis of the parkin gene(PARK2) exon 1-12 dosage.BMC Medical Genetics,2007;8:6 doi:10.1186/1471-2350-8-6.
[46]Paisan-Ruiz C,et al.Characterization of PLA2G6 as a locus for dystonia-parkinsonism.Annals of Neurology,2009;65:19-23.
[47]张宝荣,宋飞,殷鑫浈,罗巍.早发性与晚发性帕金森病临床及PARKIN基因突变对照研究.中华神经科杂志,2007;40(3):199-200.
[48]Schlitter AM,Kurz M,Larsen JP,et al.Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations.J.Negat.Results Biomed.2005;4,p.10.
[49]Lucking CB,Abbas N,Durr A,et al.Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. Lancet, 1998; 352(9137):1355-1356.
[50] Klein C, Grunewald A and Hedrich K. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology, 2006; 66: 1129-1130.
[51] Rawal N, Periquet M, Lohmann E, et al. New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism. Neurology 2003; 60:1378-1381.
[52] Wu RM, Bounds R, Lincoln S, et al. Parkin mutations and early-onset Parkinsonism in a Taiwanese cohort. Arch Neurol 2005; 62:82-87.
[53] Mizuno Y, Hattori N, Kubo S, et al. Progress in the pathogenesis and genetics of Parkinson' s disease. Phil Trans R Soc B 2008; 363:2215-2227.
[54] Hilker R, Klein C, Ghaemi M, et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001; 49:367-376.
[55] Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic parkinson's disease. Neurobiol Aging 2003; 24:197-211.
[1]de Rijk MC,Tzourio C,Breteler MM,et al.Prevalence of parkinsonism and Parkinson's disease in Europe:the EUROPARKINSON Collaborative Study:European community concerted action on the epidemiology of Parkinson's disease.J Neurol Neurosurg Psychiatry 1997;62:10-5.
[2]Polymeropoulos MH,Lavedan C,Leroy E,et al.Mutation in the α-synuclein gene identified in families with Parkinson's disease.Science,1997;276:2045-2047.
[3]Kitada T,Asakawa S,Hattori N,et al.Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature,1998;392:605-8.
[4]Gasser T,M(u|¨)ller-Myhsok B,Wszolek ZK,et al.A susceptibility locus for Parkinson's disease maps to chromosome 2pl3. Nat Genet, 1998; 18:262-265.
[5] Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease [letter]. Nature, 1998; 395:451-452.
[6] Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004;304:1158-1160.
[7] Bonifati V, Rizzu P, Van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 2002; 299:256-259.
[8] Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal dominant parkinsonism with pleomorphic pathology. Neuron, 2004; 44: 601-607.
[9] Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron, 2004; 44:595-600.
[10] Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet, 2006; 38:1184-1191.
[11] Hicks AA, Petursson H., Jonsson T, et al. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol, 2002; 52:549-555.
[12] Lautier C, Goldwurm S, Durr A, et al. Mutations in the GIGYF2 (TNRC15) gene at the PARKl 1 locus in familial Parkinson disease. Am J Hum Genet, 2008; 82(4) :822-833.
[13] Pankratz N, Nichols WC, Uniacke SK, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Molec Genet, 2003; 12: 2599-2608.
[14] Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet, 2005; 14:2099-2111.
[15] Paisan-Ruiz C, et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of Neurology, 2009; 65:19-23.
[16] Di Fonzo A, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology, 2009; 72:240-245.
[17] Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, et al. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochem Biophys Res Commun,1996; 226:561-565. (doi:10.1006/bbrc. 1996.1394)
[18] Matsumine H. et al. Localization of a ene for autosomal recessive form of juvenile Parkinsonism (AR-JP) to chromosome 6q25.2-27. Am J Hum Genet, 1997;60:588-596.
[19] Matsumine H, Yammaura Y, Hattori N, Kobayashi, T & Mizuno Y. A microdeletion spanning D6S305 co-segregates with autosomal recessive juvenile Parkinsonism (ARJP). Genomics, 1998; 49: 143-146. (doi:10.1006/geno.1997. 5196)
[20] Asakawa S. et al. Human BAC library, construction and rapid screening. Gene,1997; 191: 69-79. (doi:10.1016/S0378-1119(97)00044-9)
[21] Hattori N, Matsumine H, Asakawa S, et al. Point mutations (Thr240Arg and Gln311 Stop) [correction of Thr240Arg and Ala311 Stop] in the Parkin gene. Biochem Biophys Res Commun, 1998; 249(3):754-758.
[22] Abbas N, Lucking CB, Ricard S, et al. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet, 1999; 8(4):567-574.
[23] Lucking CB, Abbas N, Durr A, et al. Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. Lancet, 1998; 352(9137): 1355-1356.
[24] Guo JF, Xiao B, Liao B, et al. Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese patients with autosomal recessive early-onset parkinsonism. Mov Disord, 2008; 23:2074-2093.
[25] Lee MJ, Mata IF, Lin CH, et al. Genotype-phenotype correlates in Taiwanese patients with early-onset recessive parkinsonism. Mov Disord, 2009; 24:104-108.
[26] Wang T, Liang Z, Sun S, et al. A novel point mutation in parkin gene was identified in an early-onset case of Parkinson's disease. Zhonghua Yi Xue Yi Chuan Xue ZaZhi, 2003; 20:111-113.
[27] Yin Chan DK, Mok V, Ng PW, et al. PARK2 mutations and clinical features in a Chinese population with early-onset Parkinson's disease. J Neural Transm, 2008; 115:715-719.
[28] Lucking CB, Durr A, Bonifati V, et al. Association between Early-Onset Parkinson's Disease and Mutation in the Parkin Gene. N Eng J Med, 2000; 342(21):1560-156.
[29] Hedrich K, Marder K,Harris J., et al. Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutatuins. Neurology, 2002; 58(8):1239-124.
[30] Thomas G. Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med, published online 27 July 2009, DOI: 10.1077/S1462399409001148.
[31] Shimura H, et al. Familial Parkinson's disease gene product, Parkin, is a ubiquitin-protein ligase. Nat Genet, 2000; 25:302-305. (doi:10.1038/77060)
[32] Mizuno Y, Hattori N, Kubo S, et al. Progress in the pathogenesis and genetics of Parkinson's disease. Phil Trans R Soc B, 2008; 363:2215-2227.
[33] Henn IH, Bouman L, Schlehe JS, et al. Parkin mediates neuroprotection through activationof IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci., 2007; 27:1868-1878.
[34] Kuroda Y, Mitsui T, Kunishige M, et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet, 2006; 15:883-895.
[35] Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin. Proc Natl Acad. Sci USA, 2006; 103:10793-10798.
[36] Ved R, et al. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of a-synuclein, parkin and DJ-1 in Cemorhabditis elegans. J Biol Chem, 2005; 280:42 655-42 668. (doi:10.1074/jbc.M505910200)
[37] Creene JC, Whitworth AJ, Kuo I, et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA, 2003; 100:4078-4083. (doi:10.1073/pnas.0737556100)
[38] Clark IE, Dodson MW, Jiang G, et al. Drosophila pinkl is required for mitochondrial function and interacts genetically with Parkin. Nature, 2006; 441:1162-1166. (doi: 10.1038/nature04779)
[39] Park J, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by Parkin. Nature, 2006; 441:1157-1161. (doi:10.1038/ nature04788)
[40] Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene, 2001; 20:4457-4465.
[41] Klein C, Grunewald A and Hedrich K. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology, 2006; 66: 1129-1130.
[42] Tan EK, Yew K, Chua E, et al. PINK1 mutations in sporadic early-onset Parkinson's disease. Mov Disord, 2006; 21:789-793.
[43] Biskup S, Gerlach M, Kupsch A, et al. Genes associated with Parkinson syndrome. J Neurol, 2008; 255:8-17.
[44] Li Y, et al. Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset Parkinsonism. Neurology, 2005; 64:1955-1957.
[45] Pridgeon JW, Olzmann JA, Chin LS, et al. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol, 2007; 5:el72.
[46] Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin. Proc Natl Acad Sci U S A, 2006; 103:10793-10798.
[47] Exner N, Treske B, Paquet D, et al. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci, 2007; 27:12413-12418.
[2] Mata IF, Lockhart PJ, Farrer MJ. Parkin genetics: one model for Parkinson's disease. Hum Mol Genet, 2004; 13:R127-R133.
[3] Lucking CB, Durr A, Bonifati V, et al; French Parkinson's Disease Genetics Study Group. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med, 2000; 342:1560-1567.
[4] Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson disease. Arch Neurol, 2005; 62:353-357.
[5] Gasser T. Mendelian forms of Parkinson's disease. Biochimica et Biophysica Acta, 2009; 1792:587-596.
[6] Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science, 1997; 276:2045-2047.
[7] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 1998;392:605-8.
[8] Gasser T, Müller-Myhsok B, Wszolek ZK, et al. A susceptibility locus for Parkinson's disease maps to chromosome 2pl3. Nat Genet, 1998; 18:262-265.
[9] Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease [letter]. Nature, 1998; 395:451-452.
[10] Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004; 304:1158-1160.
[11] Bonifati V, Rizzu P, Van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 2002; 299:256-259.
[12] Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron, 2004; 44: 601-607.
[13] Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron, 2004; 44:595-600.
[14] Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet, 2006;38: 1184-1191.
[15] Hicks AA, Petursson H., Jonsson T, et al. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol, 2002; 52:549-555.
[16] Lautier C, Goldwurm S, Durr A, et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet, 2008; 82(4):822-833.
[17] Pankratz N, Nichols WC, Uniacke SK, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Molec Genet, 2003; 12: 2599-2608.
[18] Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet, 2005; 14:2099-2111.
[19] Paisan-Ruiz C, et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of Neurology, 2009; 65:19-23.
[20] Di Fonzo A, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology, 2009; 72:240-245.
[21] Gasser T. Mendelian forms of Parkinson's disease. Biochim Biophys Acta, published online 2009, doi: 10.1016/j.bbadis.2008.12.007.
[22] Hattori N, Kitada T, Matsumine H, et al. Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals. Ann Neurol, 1998; 44:935-41.
[23] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 1998; 392:605-608.
[24] Lucking CB, Bonifati V, Periquet M, et al. Pseudo- dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology, 2001; 57: 924-927.
[25] Foroud T, Uniacke SK, Liu L, et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology, 2003; 60:796 - 801.
[26] Pankratz N, Foroud T. Genetics of Parkinson disease. The American Society for Experimental Neuro Therapeutics, 2004; 1:235-242.
[27] Biskup S, Gerlach M, Kupsch A, et al. Genes associated with Parkinson syndrome. J Neurol, 2008; 255[suppl5]:8-17.
[28] Hattori N, Matsumine H, Asakawa S, et al. Point mutations (Thr240Arg and Ala311Stop) in the parkin gene. Biochem Biophys Res Commun, 1998; 249:754-8. [Erratum, Biochem Biophys Res Commun 1998; 251:666].
[29] Livak KJ, Schmittgen TD. Analysisof relative gene expression data using real-time quantitative PCR and the 2~(-KKCT) method. Methods, 2001; 25:402-408.
[30] Abou-Sleiman PM, Muqit MM, Wood NM. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci, 2006; 7:207-219.
[31] Mizuno Y, Hattori N, Kubo S, et al. Progress in the pathogenesis and genetics of Parkinson's disease. Phil Trans R Soc B, 2008; 363:2215-2227.
[32] Li Y, et al. Clinicogenetic study of PINKl mutations in autosomal recessive early-onset Parkinsonism. Neurology, 2005; 64:1955-1957.
[33] Guo JF, Xiao B, Liao B, et al. Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese patients with autosomal recessive early-onset parkinsonism. Mov Disord, 2008; 23:2074-2093.
[34] Lee MJ, Mata IF, Lin CH, et al. Genotype-phenotype correlates in Taiwanese patients with early-onset recessive parkinsonism. Mov Disord, 2009; 24:104-108.
[35] Tan EK, Yew K, Chua E, et al. PINKl mutations in sporadic early-onset Parkinson's disease. Mov Disord, 2006; 21:789-793.
[36] Silvestri L, Caputo V, Bellacchio E, et al. Mitochondrial import and enzymatic activity of PINKl mutants associated to recessive parkinsonism. Hum Mol Genet, 2005; 14:3477-3492.
[37] Sim CH, Lio DS, Mok SS, et al. C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet, 2006; 15:3251-3262.
[38] Petit A, Kawarai T, Paitel E,et al.Wild-type PINKl prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem, 2006; 280:34025-34032.
[39] Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin. Proc Natl Acad Sci USA, 2006; 103:10793-10798.
[40]Clark IE,Dodson MW,Jiang C,et al.Drosophila pinkl is required for mitochondrial function and interacts genetically with parkin.Nature,2006;441:1162-1166.
[41]Park J,Lee SB,Lee S,et al.Mitochondrial dysfunction in Drosophila PINK1mutants is complemented by parkin.Nature,2006;441:1157-1161.
[42]Tang B,Xiong H,Sun P,et al.Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.Hum Mol Genet,2006;15:1816-1825.
[43]Wang T,Liang Z,Sun S,et al.A novel point mutation in parkin gene was identified in an early-onset case of Parkinson's disease.Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2003;20:111-113.
[44]Yin Chan DK,Mok V,Ng PW,et al.PARK2 mutations and clinical features in a Chinese population with early-onset Parkinson's disease.J Neural Transm,2008;115:715-719.
[45]Shadrina MI,Semenova EV,Slominsky PA,et al.Effective quantitative real-time polymerase chain reaction analysis of the parkin gene(PARK2) exon 1-12 dosage.BMC Medical Genetics,2007;8:6 doi:10.1186/1471-2350-8-6.
[46]Paisan-Ruiz C,et al.Characterization of PLA2G6 as a locus for dystonia-parkinsonism.Annals of Neurology,2009;65:19-23.
[47]张宝荣,宋飞,殷鑫浈,罗巍.早发性与晚发性帕金森病临床及PARKIN基因突变对照研究.中华神经科杂志,2007;40(3):199-200.
[48]Schlitter AM,Kurz M,Larsen JP,et al.Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations.J.Negat.Results Biomed.2005;4,p.10.
[49]Lucking CB,Abbas N,Durr A,et al.Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. Lancet, 1998; 352(9137):1355-1356.
[50] Klein C, Grunewald A and Hedrich K. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology, 2006; 66: 1129-1130.
[51] Rawal N, Periquet M, Lohmann E, et al. New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism. Neurology 2003; 60:1378-1381.
[52] Wu RM, Bounds R, Lincoln S, et al. Parkin mutations and early-onset Parkinsonism in a Taiwanese cohort. Arch Neurol 2005; 62:82-87.
[53] Mizuno Y, Hattori N, Kubo S, et al. Progress in the pathogenesis and genetics of Parkinson' s disease. Phil Trans R Soc B 2008; 363:2215-2227.
[54] Hilker R, Klein C, Ghaemi M, et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001; 49:367-376.
[55] Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic parkinson's disease. Neurobiol Aging 2003; 24:197-211.
[1]de Rijk MC,Tzourio C,Breteler MM,et al.Prevalence of parkinsonism and Parkinson's disease in Europe:the EUROPARKINSON Collaborative Study:European community concerted action on the epidemiology of Parkinson's disease.J Neurol Neurosurg Psychiatry 1997;62:10-5.
[2]Polymeropoulos MH,Lavedan C,Leroy E,et al.Mutation in the α-synuclein gene identified in families with Parkinson's disease.Science,1997;276:2045-2047.
[3]Kitada T,Asakawa S,Hattori N,et al.Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature,1998;392:605-8.
[4]Gasser T,M(u|¨)ller-Myhsok B,Wszolek ZK,et al.A susceptibility locus for Parkinson's disease maps to chromosome 2pl3. Nat Genet, 1998; 18:262-265.
[5] Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease [letter]. Nature, 1998; 395:451-452.
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