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Role of parkin mutations in 111 community-based patients with early-onset parkinsonism 总被引:9,自引:0,他引:9
Kann M Jacobs H Mohrmann K Schumacher K Hedrich K Garrels J Wiegers K Schwinger E Pramstaller PP Breakefield XO Ozelius LJ Vieregge P Klein C 《Annals of neurology》2002,51(5):621-625
Early-onset parkinsonism is frequently reported in connection with mutations in the parkin gene. In this study, we present the results of extensive genetic screening for parkin mutations in 111 community-derived early-onset parkinsonism patients (age of onset <50 years) from Germany with an overall mutation rate of 9.0%. Gene dosage alterations represented 67% of the mutations found, underlining the importance of quantitative analyses of parkin. In summary, parkin mutations accounted for a low but significant percentage of early-onset parkinsonism patients in a community-derived sample. 相似文献
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Nisipeanu P Inzelberg R Abo Mouch S Carasso RL Blumen SC Zhang J Matsumine H Hattori N Mizuno Y 《Neurology》2001,56(11):1573-1575
Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course. 相似文献
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The search for genetic mutations responsible for familial forms of Parkinson's disease (PD) has identified several genes and loci. Mutations in the parkin gene are linked to autosomal recessive juvenile parkinsonism. The genetic forms of PD are uncommon, but gene therapy targeting α-synuclein, parkin, or other pathways may be also applicable for idiopathic PD. Intriguingly, several studies suggest that parkin gene therapy could be useful in a subset of PD patients with mutations in the α-synuclein gene. Furthermore, if parkin overexpression can correct neuronal degeneration in the substantia nigra and striatum, it might be a potentially effective therapy for α-synucleinopathy. 相似文献
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Y Kuroda T Mitsui M Akaike H Azuma T Matsumoto 《Journal of neurology, neurosurgery, and psychiatry》2001,71(2):231-234
Autosomal recessive juvenile parkinsonism (AR-JP) is characterised by homogenous clinical features and selective degeneration of nigral neurons. Recent progress in molecular genetic analyses of AR-JP has led to the identification of a novel ubiquitin-like protein, parkin, whose precise function still remains to be elucidated. Two unrelated Japanese families had levodopa unresponsive parkinsonism complicated with cerebellar and pyramidal tract dysfunction. Genetic analysis of the parkin gene and mRNA in both families disclosed identical mutations with large deletions extending from exons 3 to 4. These results suggest that the parkin protein possesses an important function not only in the substantia nigra but also in extranigral neurons of the CNS and that the phenotype of multiple system dysfunction can also be a complication in patients with AR-JP due to variations in sites of or changes in functions by parkin mutation. 相似文献
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Mochizuki H 《Expert Review of Neurotherapeutics》2007,7(8):957-960
Advances in molecular biology and virology in recent years have enabled the technology of gene transfer to proceed forward. Parkinson's disease (PD) is a particularly appropriate target for gene therapy since the brain pathology is fully characterized and relatively well circumscribed largely within the nigrostriatal dopaminergic neurons. In addition, the search for genetic mutations responsible for familial forms of PD has accelerated in recent years with several genes or loci already identified. Mutations in the parkin gene are linked to the autosomal recessive form known as autosomal recessive juvenile parkinsonism, park2. Therefore, parkin gene therapy can be effective in PD caused by parkin gene mutations, which are inherited as an autosomal recessive trait. Intriguingly, several studies, including our reports, have suggested the possibility that parkin gene therapy could treat a subset of patients with PD who have mutations in the alpha-synuclein gene. Furthermore, if indeed parkin overexpression broadly corrects anatomical degeneration in the substantia nigra and striatum, this might be a potential therapy for alpha-synucleinopathy. 相似文献
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K Hasegawa M Funayama N Matsuura H Furusawa F Sakai H Kowa F Obata 《European neurology》2001,46(1):20-24
We examined whether autosomal dominant parkinsonism of a Japanese family, Sagamihara family, was due to the mutations of alpha-synuclein, parkin, tau, and UCH-L1, which have been reported as the causal genes for parkinsonism in other families. Restriction-enzyme digestion of polymerase-chain reaction (PCR) amplified genomic DNA fragments of alpha-synuclein exons 3 and 4 detected no point mutation. PCR-amplification of parkin exons 3, 4, 5, 6 and 7 detected no exon deletion. Direct sequencing of PCR-amplified DNA fragments of tau exons 9, 10, 12, and 13 and intron 10, and of UCH-L1 exon 4 revealed that all these exons and intron were normal including a polymorphic nucleotide substitution. These results indicated that the parkinsonism of the Sagamihara family seems not to be due to previously identified point mutations of alpha-synuclein, tau, or UCH-L1, or to exon deletion of parkin. 相似文献
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Kay DM Moran D Moses L Poorkaj P Zabetian CP Nutt J Factor SA Yu CE Montimurro JS Keefe RG Schellenberg GD Payami H 《Annals of neurology》2007,61(1):47-54
OBJECTIVE: Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects. METHODS: A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects. RESULTS: Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects. INTERPRETATION: parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined. 相似文献
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Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype 总被引:18,自引:0,他引:18
Klein C Pramstaller PP Kis B Page CC Kann M Leung J Woodward H Castellan CC Scherer M Vieregge P Breakefield XO Kramer PL Ozelius LJ 《Annals of neurology》2000,48(1):65-71
A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease. 相似文献
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Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority
of cases of inherited Parkinson’s disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly
have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however,
parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin
protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation
by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated α-synuclein, parkin associated
endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study.
Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these
highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar
to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of
PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the
pathogenesis of both familial and sporadic PD. 相似文献
11.
Mutations in the parkin gene have been significantly linked to autosomal recessive juvenile parkinsonism (ARJP). In addition to its association with ARJP, loss of heterozygosity of parkin has been found in several types of malignant tumors, including ovarian, breast, and hepatocellular tumors. Abnormal methylation of parkin promoter was observed in patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in lymphoid blast crisis. We hypothesized that hypermethylation of the parkin promoter might reduce the expression of parkin, which would contribute to the pathogenesis of parkinson's disease (PD) in idiopathic patients and parkin heterozygotes. In this study, we analyzed samples from 17 PD patients with heterozygous parkin mutations, 17 PD patients without parkin mutations, and 10 normal controls. We determined the levels of methylation of the parkin gene promoter in each group using bisulfite genomic sequencing of a region containing 33 CpG sites in the CpG island of the parkin promoter. The methylation levels indicated hypomethylation, and there were no significant differences in the incidence of CpG site methylation among three groups (P > 0.05). These results suggest that the methylation mechanism is unlikely to play a role in the pathogenesis and development of PD. 相似文献
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Wu RM Bounds R Lincoln S Hulihan M Lin CH Hwu WL Chen J Gwinn-Hardy K Farrer M 《Archives of neurology》2005,62(1):82-87
BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic "parkin-proven" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific. 相似文献
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Blas Morales Armando Martínez Isabel Gonzalo Lidice Vidal Raquel Ros Estrella Gomez-Tortosa Alberto Rabano Israel Ampuero Marina Sánchez Janet Hoenicka Justo García De Yébenes 《Movement disorders》2002,17(6):1374-1380
Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed. 相似文献
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Deciphering the role of heterozygous mutations in genes associated with parkinsonism 总被引:2,自引:0,他引:2
The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinson's disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease. 相似文献
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Pramod K Pal Joanne Leung Katya Hedrich Ali Samii Abraham Lieberman Paul A Nausieda Donald B Calne Xandra O Breakefield Christine Klein A Jon Stoessl 《Movement disorders》2002,17(4):789-794
There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene. 相似文献
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Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism
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Muñoz E Tolosa E Pastor P Martí MJ Valldeoriola F Campdelacreu J Oliva R 《Journal of neurology, neurosurgery, and psychiatry》2002,73(5):582-584
BACKGROUND: Autosomal recessive juvenile parkinsonism is a neurodegenerative disorder associated with mutations in the parkin gene. OBJECTIVES: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. METHODS: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. RESULTS: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. CONCLUSIONS: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population. 相似文献
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Bonifati V 《Parkinsonism & related disorders》2012,18(Z1):S4-S6
Several forms of autosomal recessive parkinsonism are known. In three forms, caused by mutations in parkin (PARK2), PINK1 (PARK6), or DJ-1 (PARK7), the phenotype is usually characterized by levodopa-responsive parkinsonism without atypical features. Parkin mutations are most frequent, explaining -50% of the cases with a clinical diagnosis of familial Parkinson's disease compatible with recessive inheritance and onset <45 years, and -15% of the sporadic cases with onset <45. Mutations in PINK1 and DJ-1 are less common, accounting for -1-8%, and -1-2% of the sporadic cases with early-onset. Since point mutations and genomic rearrangements can be present, sequencing and exon dosage are both required for accurate mutational screening of these genes. The phenotype of parkin mutations is characterized by early-onset parkinsonism, good response to levodopa, and benign course. The average onset age is in the 30s, but late-onset cases have been described. The phenotype associated with PINK1 and DJ-1 mutations has been studied in a smaller number of patients but it is overall indistinguishable from that of parkin. Mutations in other genes, including ATP13A2 (PARK9), PLA2G6 (PARK14), and FBX07 (PARK15), cause more rare forms of recessive parkinsonism with very early-onset (<30 years) and usually additional, atypical features (pyramidal, dystonic, ocular movement, and cognitive disturbances). Yet, it is expected that other monogenic forms of parkinsonism will be identified in the future, as mutations in the above-mentioned genes are not found in other patients with similar phenotypes. 相似文献
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Inactivating mutations of the gene encoding parkin are responsible for autosomal recessive juvenile parkinsonism (AR-JP). However, little information is known about the function and distribution of parkin. We generated antibodies to two different peptides of parkin. By Western blot analysis and immunohistochemistry, we found that parkin is a 50-kd protein that is expressed in neuronal processes and cytoplasm of selected neurons in the basal ganglia, midbrain, cerebellum, and cerebral cortex. Unlike ubiquitin and alpha-synuclein, parkin labeling was not found in Lewy bodies of four sporadic Parkinson disease brains. Parkin was colocalized with actin filaments but not with microtubules in COS1 kidney cells and nerve growth factor-induced PC12 neurons. These results point to the importance of the cytoskeleton and associated proteins in neurodegeneration. 相似文献