The G209A Mutation in the α-Synuclein Gene Is Not Detected in Familial Cases of Parkinson Disease in Non-Greek and/or Italian Populations (original) (raw)
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Low frequency of ?-synuclein mutations in familial Parkinson's disease
Annals of Neurology, 1998
A mutation in exon 4 of the α-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.
Movement Disorders, 2006
␣-Synuclein is one of the main components of Lewy bodies, a pathological marker of Parkinson's disease (PD). Certain missense mutations of the ␣-synuclein gene cause familial PD, but the role of the gene in sporadic PD is still controversial. We scrutinized polymorphisms of the ␣-synuclein gene in a Japanese population and investigated their associations with sporadic cases of PD. The 5Ј flanking region to intron 2 of the ␣-synuclein gene (3.8 kb) and two polymorphisms in intron 4 previously reported in Caucasian sporadic cases of PD were analyzed in 185 sporadic PD and 191 controls. Five novel single nucleotide polymorphisms (SNPs), 16 reported SNPs, and one reported polynucleotide polymorphism (PNP) were found. Most of the polymorphisms examined were in linkage disequilibrium. Significant associations with PD were found in 15 of 21 SNPs, especially in intron 1 (IVS1ϩ155 TmAn PNP and the IVS1ϩ719 CϾT SNP, P Ͻ 0.0001). Haplotype analysis showed that T10A7-A-A and T11A6-G-G haplotypes at three loci (IVS1ϩ155 -IVS1ϩ273 -IVS1ϩ608) were strongly negative and positive risk factors of sporadic PD, respectively (odds ratios were 0.23 [95% confidence interval, 0.16 -0.32] and 1.51 [95% confidence interval, 1.29 -1.75]). In conclusion, our findings indicate that genetic variations of the ␣-synuclein gene affect the development of sporadic PD.
Movement Disorders, 2001
Missense mutations of the α-synuclein gene have been reported to explain a few kindreds with autosomal dominant Parkinson's disease (PD). In order to identify mutations in our PD patients, we have screened the coding region and 5′flanking region of the gene. DNA samples from 50 patients with familial PD were screened via single-strand conformation polymorphism (SSCP) for mutations in the α-synuclein gene. The 5′ flanking region was examined in 117 additional PD patients (27 patients with unclear family history for PD, and 90 patients without family history) and in 169 control subjects. We found one change (G199A) in exon 4 in one family with a pattern of autosomal dominant PD. However, this mutation did not result in an amino acid substitution (valine) and did not segregate completely with PD. The analysis of the 5′ flanking region also showed a new polymorphism, a nucleotide insertion (− 164insA) linked to a nucleotide substitution (C−116G), in patients and in controls. The −164insA/C−116G allele was present in 52.3% of the patients and in 47.6% of the controls. We did not find significant differences regarding the allelic and genotype frequencies between PD and control groups. These results suggest that mutations in the α-synuclein gene are a very rare cause of familial PD and that the novel −164insA/C−116G polymorphism in the 5′ flanking region does not confer susceptibility to develop PD. © 2001 Movement Disorder Society.
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Science, 1997
Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
Neuroscience Letters, 1997
We initiated the present work in order to determine if the Ala53Thr mutation of the a-synuclein gene previously described by Polymeropoulos et al. [Science, 276 (1997) 2045-2047 could be detected in Spanish early onset Parkinson's disease (PD) patients. Thirty-four PD patients were evaluated. Of these, 13 were considered early onset patients (six familial and seven sporadic) and were included in the genetic study. We detected the presence of genetic anticipation in four kindreds with early onset PD members. The Ala53Thr mutation of the a-synuclein gene was absent in all patients. The results do not support a role for this mutation in our patients with early onset PD and, in agreement with the results previously reported, indicate that the Ala53Thr mutation of the a-synuclein gene is a rare cause of PD.
Reduced expression of the G209A ?-synuclein allele in familial parkinsonism
Annals of Neurology, 1999
Missense mutations at the ␣-synuclein gene have been associated with familial parkinsonism. We report that the phenotype of a kindred (Family H) with autosomal dominant, levodopa-responsive parkinsonism maps to chromosomal region 4q21-23 and that affected members of this kindred harbor a previously reported mutation (G209A) in exon 4 of the ␣-synuclein gene. We assessed the expression of the G209A allele in lymphoblastoid cell lines established from 12 individuals heterozygous for the G209A allele. The expression of this allele is either absent or significantly reduced in 7 affected heterozygotes and in 3 asymptomatic heterozygotes who are older than the mean age at disease diagnosis for their generation. In contrast, it is expressed in 1 affected and 1 unaffected heterozygote. The unaffected heterozygote is younger than the mean age at disease diagnosis for their generation. The lack of or significantly reduced expression of the G209A allele in affected heterozygotes suggests that the timing of reduced expression may be critical for disease onset. If so, the parkinsonian phenotype may arise from haploinsufficiency at the ␣-synuclein gene at a time point before symptom onset. In conclusion, reduced ␣-synuclein gene expression may be important in the pathogenesis of parkinsonism.