Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease

Juntendo University, Edo, Tōkyō, Japan
Annals of Neurology (Impact Factor: 9.98). 02/2006; 59(2):298-309. DOI: 10.1002/ana.20753
Source: PubMed


Recently, genomic multiplications of alpha-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD).
We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by fluorescence in situ hybridization (FISH) and comparative genomic hybridization array.
Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCA duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCA multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected.
These two newly identified Japanese patients with SNCA duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated.

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    • "Asymptomatic carriers and intrafamilial variability found in PD pedigrees with SNCA duplications suggested that in addition to copy number variations, other factors, such as another genetic variability of the SNCA gene, genetic modifiers, genetic background or environmental exposures, could influence the development of symptoms in subjects with SNCA duplications (Ahn et al., 2008; Elia et al., 2013; Nishioka et al., 2009, 2006). A direct relation between SNCA gene dosage and age at disease onset, the disease severity and progression was reported (Ahn et al., 2008; Chartier-Harlin et al., 2004; Ibáñez et al., 2009, 2004; Ikeuchi et al., 2008), and the phenotype of the SNCA duplication may also be influenced by the range of duplication region (Nishioka et al., 2006). "
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    ABSTRACT: Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
    Ageing research reviews 04/2014; 15(1). DOI:10.1016/j.arr.2014.04.002 · 4.94 Impact Factor
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    • "Several point mutations in the SNCA gene and duplications and triplications of the genomic region containing SNCA were revealed. They are very rare and lead to the development of an autosomal dominant form of PD [7] [8] [9] [10] [11]. "
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    ABSTRACT: Parkinson’s disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the pathogenesis of PD. In our study, we conducted a genetic analysis of promoter and intron single-nucleotide polymorphisms (SNPs) in the SNCA gene. We also analyzed the association of genotypes of these SNPs with expression levels of SNCA mRNA. One of the four SNPs in the SNCA gene, the rs2736990 polymorphism, associates with the risk of the sporadic form of PD in Russian population. The risk of PD was increased almost twofold in carriers of allele C (odds ratios = 1.9, 95% confidence interval: 1.24 - 2.91, p = 0.003). However, no association was found between any of the genotypes of SNPs tested (rs2583988, rs2619363, rs2619364 and rs2736990) and alterations in SNCA levels. Our findings support the hypothesis that the rs2736990 polymorphism is associated with PD. SNPs rs2583988, rs2619363 and rs2619364 in the promoter region of the SNCA gene themselves, and do not significantly influence the expression of SNCA. Most likely, SNCA gene expression is a very complex process that is affected by different genetic and epigenetic factors.
    Neuroscience & Medicine 12/2013; 4(4):208-214. DOI:10.4236/nm.2013.44032
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    • "RESEARCH ARTICLE forms of a-synuclein are implicated in neurodegeneration in Parkinson's disease. Mutations in SNCA, the gene encoding a-synuclein, including a base substitution (A53T) (Polymeropoulos et al., 1997), two point mutations (A30P and E46K) (Kruger et al., 1998; Zarranz et al., 2004), as well as gene duplications and triplications (Singleton et al., 2003; Nishioka et al., 2006), can cause Parkinson's disease. Posttranslational modifications to a-synuclein, including truncation (Liu et al., 2005), nitration (Giasson et al., 2000), and hyperphosphorylation (Anderson et al., 2006), are also implicated in the disease pathogenesis. "
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    ABSTRACT: Parkinson's disease is a neurodegenerative disorder characterised by motor and non-motor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α-synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea-pig rectum and human colon expressed α-synuclein in their axons. α-Synuclein-immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)-IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea-pig rectal myenteric ganglia. However, α-synuclein-immunoreactivity was localised in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 ± 3%, p <0.001). Of SOM-IR, SP-IR and VIP-IR varicosities that lacked VAChT-immunoreactivity, only 1 ± 0.3%, 0 ± 0.3% and 0% contained α-synuclein-immunoreactivity, respectively. 71 ± 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were α-synuclein-IR. In guinea-pig rectal myenteric ganglia, α-synuclein- and VAChT-immunoreactivity co-existed in 15 ± 1.4% of biotinamide-labeled extrinsic varicosities; only 1 ± .3% of biotinamide-labeled extrinsic varicosities contained α-synuclein-immunoreactivity without VAChT-immunoreactivity. α-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective α-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 02/2013; 521(3). DOI:10.1002/cne.23198 · 3.23 Impact Factor
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