A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson's disease in a Japanese population

Recent studies suggest that ubiquitin C-terminal hydrolase-L1 (UCH-L1), a neuronal deubiquitinating enzyme, represents a candidate gene responsible for either the development of familial Parkinson's disease (PD) or the protection against sporadic PD in Caucasian populations, although these findings are not fully verified in non-Caucasian populations. To determine an association of the variations in the UCH-L1 gene with development of sporadic PD in a Japanese population, a Ser18Tyr polymorphism and an Ile93Met mutation were studied by PCR-RFLP analysis in 74 Japanese patients with sporadic PD and 155 age-matched non-PD controls. The frequency of 18Tyr allele was significantly lower in PD patients than the controls (38.5% vs. 53.5%) (chi(2)=9.064, p=0.0026; the odds ratio=1.84, 95% confident interval=1.23-2.74). Furthermore, the frequency of 18Tyr/Tyr homozygotes was significantly lower in PD patients than the controls (14.9% vs. 33.5%), compared with that of two other genotypes combined (chi(2)=8.767, p=0.0031; the odds ratio=0.35, 95% confident interval=0.27-0.45). The Ile93Met substitution was not detected in any Japanese subjects examined. These results indicate that the presence of 18Tyr allele and 18Tyr/Tyr homozygosity in the UCH-L1 gene is associated with a reduced risk for development of sporadic PD in a Japanese population, supporting the previous observations on sporadic PD in Caucasian populations.     

Progress in familial Parkinson's disease

To date 11 forms of familial Parkinson's disease (PD) have been mapped to different chromosome loci, of which 6 genes have been identified as the causative genes, i.e., alpha-synuclein (SNCA), parkin, UCH-L1, PINK1, DJ-1, and LRRK2. For UCH-L1, additional families with this mutation are necessary before concluding that UCH-L1 is the definite causative gene for PARK5, as only one family so far has been reported. SNCA, UCH-L1, and LRRK2 mutations cause autosomal dominant PD and the remaining gene mutations autosomal recessive PD. Age of onset tends to be younger in familial PD compared with sporadic PD, particularly so in autosomal recessive PD. Generally familial cases respond to levodopa quite nicely and progression of the disease tends to be slower. It is an interesting question how familial PD-causing proteins are mutually related each other. In this article, we review recent progress in genetics and molecular biology of familial PD.     

No genetic association of the Ubiquitin Carboxy-terminal Hydrolase-L1 gene S18Y polymorphism with familial Parkinson's disease

Summary. Parkinson's disease (PD) is a neurodegenerative disorder for which genetic susceptibility has been documented in sporadic and familial cases. Recently, a polymorphism located in exon 3 at codon 18 (S18Y) of the Ubiquitin Carboxy-terminal Hydrolase-L1 (UCH-L1) gene has been associated with the disease in 2 populations of German origin and also in a Japanese population. We tested the impact of this polymorphism in a French sample of familial PD patients (n = 114) and controls (n = 93). No association was observed, indicating that this polymorphism did not confer susceptibility for familial PD in our population, even among the youngest age of onset group. This observation suggests that the previous positive results obtained may reflect mechanisms restricted to the sporadic form of the disease or to a founder effect of the disease susceptibility. Received February 21, 2001; accepted April 9, 2001     

Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinson's disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36-0.88; p = 0.012, p(c) = 0.047, chi2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration.     

Association between a polymorphism of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene and sporadic Parkinson's disease

We found a novel polymorphism (S/Y18) of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene a mutation of which is expected to contribute to the etiology of a form of familial Parkinson's disease (PD). We report the frequency of this polymorphism in 313 patients with sporadic PD and 302 control subjects (Japanese and Caucasians). The frequency of the mutant allele (Y) was significantly higher in Japanese control subjects (51.2%) than in Japanese PD patients (43.4%) (χ²=3.917, p=0.048<0.05). It appears that this polymorphism has a weak protective factor against PD in at least the Japanese population. The frequencies of Y allele and S/Y and Y/Y genotypes in the PD patients and the controls were more significantly higher in Japanese than in Caucasian population (p<0.0001). It seems that the role of this polymorphism in PD may be different between Caucasian and Japanese populations.     

Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance?

The G209A mutation in the alpha-synuclein gene has been associated with autosomal dominant PD (ADPD) in a family from Contursi, Italy, and three apparently unrelated Greek families. Several groups around the world failed to identify the G209A mutation in a sizable series of familial and sporadic cases of PD. The authors present two additional Greek families with ADPD associated with the G209A mutation. In both families, asymptomatic carriers older than the expected age at onset were found.     

Linkage exclusion in French families with probable Parkinson' s disease.

We analyzed the segregation of genetic markers spanning chromosomal regions 2p13, 4p14-15, 4q21-23, 6q25-27, and 17q21 in nine French families affected by autosomal-dominant probable Parkinson's disease. These regions have been linked or associated with familial Parkinson's disease. Multipoint linkage and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine families. For three families, which were equivocal for two-point linkage at D4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-L1) was sequenced. In one family, a novel UCH-L1 M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in this gene may not be pathogenic. In seven of nine families, it could be inferred that affected individuals did not share 4q21-23 (alpha-synuclein) haplotypes. All families were unequivocally excluded by haplotype analysis from the parkin locus on 6q25-27. Finally, the 17q21 region was excluded in four of nine families, and no mutation in the tau gene was identified in the five remaining families. Findings from this study confirm genetic heterogeneity within familial parkinsonism.     

The G2019S LRRK2 mutation is uncommon amongst Greek patients with sporadic Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 2% of the population >60 years of age. Although, the etiology of PD is still unknown, the genetic background of the disease has been documented. Recently, a mutation in the LRRK2 gene, G2019S, was associated with 3–41% and 1–2% of familial and sporadic PD, respectively suggesting a pivotal role of LRRK2 in PD. In this report, we examine the association of the G2019S mutation with sporadic late-onset PD, in an independent cohort of Greek patients and controls.     

Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques.

The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinson's disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non-Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele-specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing. In addition to 22 members of the original Basque families where R1441G was identified, we observed 17 carriers of the mutation who were apparently related through a common ancestor. From a clinical perspective, the disease observed in mutation carriers is indistinguishable from that in noncarriers. The R1441G mutation causes a form of Parkinson's disease that is equivalent to that observed in idiopathic Parkinson's disease. This mutation appears in 16.4% and 4.0% of familial and sporadic PD in this Basque population, respectively.     

家族性帕金森病患者parkin基因缺失突变的初步研究

目的 探讨中国家族性帕金森病（PD）患者parkin基因第3-7外显子是否存在缺失突变，及其与该病临床特点的关系。方法 采集6例无血缘相关的家族性PD患者外周血液，提取DNA，通过PCR扩增，琼脂糖凝胶电泳鉴定parkin基因第3-7外显子缺失突变，并结合临床资料分析。结果 6例患者中，发现1例有第5外显子缺失，其遗传模式呈常染色体隐性遗传，起病年龄60岁，临床表现为震颤，僵直和运动迟缓，但无异动症，第3、4、6、7外显子未发现缺失突变。结论 中国家族性PD患者中存在parkin基因和5外显子缺失突变改变。     

An analysis of genetic studies of Parkinson's disease in Africa

Online databases (till April 30, 2007) revealed 12 studies describing genetics of Parkinson's disease (PD) in Africa. Two studied inheritance patterns of familial PD. Ten focused on one of three genes, i.e. parkin, PINK 1 and LRRK2 in familial PD. Most studies were from North Africa, where parkin mutations are the most common cause of autosomal recessive PD. Frequency of LRRK2 G2019S mutation is higher than North American and European populations. The LRRK2 G2019S mutation is frequent in apparently sporadic PD in North Africans. There is a need to extend research into genetics of sporadic and familial PD to more African subregions.     

A valine to methionine polymorphism at codon 83 in the 8-oxo-dGTPase gene MTH1 is not associated with sporadic Parkinson''s disease

Recently, 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase; MTH1), a key enzyme for preventing oxidative stress-induced DNA damage, has been found to be expressed aberrantly in the nigrostriatal dopaminergic neurones in the brains of those with Parkinson's disease (PD). A valine (Val) to methionine (Met) polymorphism at codon 83 in exon 4 of the MTH1 gene was studied in 73 patients with sporadic PD and 151 age-matched non-PD controls by PCR-RFLP analysis, to determine a possible association of this polymorphism with development of PD. The frequency of either 83Val or 83Met allele was not statistically different between PD patients (92.5% or 7.5%) and the controls (88.7% or 11.3%) (chi(2) = 1.511, P = 0.2190). The 83Met/Met homozygotes consisting of an infrequent genotype in the control population (1.3%) were not found in the PD group. The frequency of both 83Val/Met heterozygotes and 83Met/Met homozygotes combined was not statistically different between PD patients (15.1%) and the controls (21.2%), compared with that of the 83Val/Val homozygotes (chi(2) = 1.190, P = 0.2754). These results indicate that the 83Val/Met polymorphism in the MTH1 gene is not associated with an increased risk for development of sporadic PD.     

Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation

Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders. We report here the immunohistochemical, biochemical and ultrastructural characterization of alpha-syn neuropathology in a case of familial PD with the A53T alpha-syn gene mutation. Insoluble filamentous alpha-syn lesions were detected in almost all brain regions examined and as in sporadic PD, we observed the accumulation of insoluble nitrated alpha-syn in this familial disorder. Significant accumulations of filamentous insoluble tau protein also were detected in some brain regions of this patient, suggesting a role for A53T mutant alpha-syn in tau fibrillization. Indeed, in vitro studies of tau and alpha-syn fibrillization showed that the A53T mutation accelerated alpha-syn fibril formation, initiated tau assembly into filaments and synergistically enhanced fibrillization of both tau and alpha-syn. Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.     

Mutation analysis of the PINK1 gene in Southern Italian patients with early- and late-onset parkinsonism

Mutations in the PINK1 gene represent the second most frequent cause of early-onset Parkinson's disease (EOPD). One or two mutated alleles were also reported in some sporadic or familial patients suffering from late-onset Parkinson's disease (LOPD). We aimed at assessing the frequency of mutations in this gene in our population. We performed a sequence analysis of PINK1 in 115 patients diagnosed with Parkinson's disease (PD) from southern Italy, including 93 sporadic cases with EOPD, 9 familial cases with EOPD, and 13 familial cases with LOPD. Three known homozygous mutations (Q456X, W437X, Q126P), corresponding to a 2.6% of all cases, were found. In particular, one mutation was detected among the sporadic cases (1.0%), one mutation among the familial early-onset patients (11.1%) and one mutation among the familial late-onset patients (7.7%). In addition, we found two heterozygous mutations (E476K, R207Q) among the sporadic patients. Only one mutation (R207Q) had not been previously described. Our results assess the role played by PINK1 in EOPD in southern Italy and illustrate the existence of mutations in this gene also in the late-onset form of the disease.     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

Clinical characteristics of the alpha-synuclein mutation (G209A)-associated Parkinson''s disease in comparison with other forms of familial Parkinson''s disease in Greece

An Ala53Thr mutation of the alpha-synuclein has been recently identified as a rare cause of familial Parkinson's disease (fPD). In the present study, the clinical characteristics of Parkinson's disease (PD) patients with Ala53Thr alpha-synuclein mutation (alpha-synPD) were compared with fPD patients without any known mutation. An investigator blinded to the results of the genetic analysis examined 15 alpha-synPD patients and 43 consecutive fPD patients. Demographic data, age at onset of the illness, duration of the disease and modality of presentation were collected. Segregation ratios for both sexes in individuals at risk of developing alpha-synPD were estimated. The Unified Parkinson's disease rating scale (UPDRS) was also completed. The 15 alpha-synPD patients were matched for duration of the disease and age at onset with 15 of the 43 fPD patients (MfPD). Comparisons were also made between 14 patients belonging to three multicase families with patterns of inheritance similar to alpha-synPD. The alpha-synPD patients were significantly younger (mean difference 11.8 years) and showed the first sign of the disease earlier in life (mean difference 12.7 years) as compared with the fPD patients. Tremor at onset was present in only one (6.7%) of the alpha -synPD patients compared with 18 (41.9%) of the fPD patients (P = 0.01). At the time of examination rigidity, postural instability, orthostatic hypotension and the overall clinical severity did not differ significantly either between alpha-synPD and fPD or between alpha-synPD and MfPD groups. Nevertheless, some clinically relevant trends concerning the psychiatric symptoms and complications of therapy were recognized. The overall clinical severity and the progression of the disease in patients with alpha-synPD did not differ from that of the fPD patients. The alpha-synPD patients presented the illness at a younger age and also had lower prevalence of tremor when compared with the fPD patients.     

G309D and W437OPA PINK1 mutations in Caucasian Parkinson's disease patients

OBJECTIVE: To determine whether the G309D and W437OPA mutations in PINK1 gene are present in American Caucasian population of patients with Parkinson's disease (PD). METHODS: We searched for the G309D and W437OPA mutation by sequencing the regions of interest in the PINK1 gene in 237 unrelated Caucasian patients. RESULTS: None of the 237 samples showed the G309D or W437OPA mutations. CONCLUSIONS: The G309D and W437OPA mutations in PINK1 gene probably do not represent common causes of familial or sporadic PD in a Caucasian population.     

Parkin gene variations in late-onset Parkinson's disease: comparison between Norwegian and German cohorts

OBJECTIVES: Mutations in the Parkin gene can cause autosomal recessive early-onset Parkinson's disease (PD). Recently, Parkin mutations were also suggested to play a role in the commoner late-onset forms of PD. METHODS: We compared a German cohort of PD patients (95) with a Norwegian cohort of PD patients (96). Both cohorts have predominant late-onset form of PD. Mutation and polymorphism frequencies were compared via single-strand conformation polymorphism and sequence analyses. RESULTS: Three heterozygous missense mutations (Arg256Cys, Arg402Cys and Thr240Met) were found in late-onset PD patients in the German patient cohort (1.6%). A missense mutation (Arg402Cys) was also found in one of 149 healthy control subjects (0.3%). Only one heterozygous missense mutation (Arg256Cys) was identified in a Norwegian patient suffering from late-onset PD (0.5%). The frequencies of four known single nucleotide polymorphisms significantly differ between the two distant European populations. CONCLUSION: The results support the hypothesis that heterozygous mutations in the Parkin gene may act as susceptibility alleles for late-onset forms of PD in rare cases.     

Translated mutation in the Nurr1 gene as a cause for Parkinson's disease.

Multiple genes have been now identified as causing Parkinson's disease (PD). In 2003, two mutations were identified in exon 1 of the Nurr1 gene in 10 of 107 individuals with familial PD. To date, investigators have only focused on screening for these known mutations of the Nurr1 gene. All individuals were recruited from two Parkinson's disease clinics in Canada. Following PCR amplification of each exon of the Nurr1 gene, samples underwent denaturing high-performance liquid chromatography (DHPLC) analysis. Ten individuals also underwent direct sequencing as well as any samples where variants were identified. The Nurr1 gene was evaluated for 202 PD individuals, 37% of whom had at least one relative with PD and 100 control non-PD individuals. Using DHPLC and direct sequencing, we did not detect any sequence variants in exon 1. Variants in amplicon 6 were seen and direct sequencing confirmed a known NI6P polymorphism in intron 6. Novel polymorphisms were also identified in exon 3 and intron 5. A novel mutation was identified in exon 3 in one nonfamilial PD individual. This heterozygous C-to-G transversion resulted in a serine-to-cysteine substitution and was not identified in any of the other 602 chromosomes screened. Mutations in the Nurr1 gene in our large cohort of familial and sporadic PD individuals are rare. The novel mutation in exon 3 is predicted to affect phosphorylation and functional studies to assess this are underway. This is the first coding mutation identified in the Nurr1 gene for Parkinson's disease.