α-synuclein gene rearrangements in dominantly inherited parkinsonism: Frequency, phenotype, and mechanisms

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR)_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
Archives of neurology (Impact Factor: 7.42). 02/2009; 66(1):102-8. DOI: 10.1001/archneurol.2008.555
Source: PubMed


Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism.
Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California).
Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened.
Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement.
Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.

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    • "Genetic analyses have revealed widely variable sizes of the duplicated genomic region, ranging from 0.2 to 41.2 Mb and containing anywhere from 2 to 150 genes [11e13]. Combined with haplotype analyses, this data indicates there is no common ancestor but duplications have arisen independently in most of the families reported [12]. The fact that sporadic cases and asymptomatic carriers have been found indicates that the penetrance is incomplete and likely age-dependent. "
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    ABSTRACT: The discovery in 1997 that mutations in the SNCA gene cause Parkinson's disease (PD) greatly advanced our understanding of this illness. There are pathogenic missense mutations and multiplication mutations in SNCA. Thus, not only a mutant protein, but also an increased dose of wild-type protein can produce autosomal dominant parkinsonism. We review the literature on SNCA duplications and focus on pathologically-confirmed cases. We also report a newly-identified American family with SNCA duplication whose proband was autopsied. We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia. Only a few cases have presented with typical features of PD. Our case presented with depression and RBD that preceded parkinsonism, and dysautonomia that led to an initial diagnosis of multiple system atrophy. Dementia and visual hallucinations followed. Our patient and the other reported cases with SNCA duplications had widespread cortical Lewy pathology. Neuronal loss in the hippocampal cornu ammonis 2/3 regions were seen in about half of the autopsied SNCA duplication cases. Similar pathology was also observed in SNCA missense mutation and triplication carriers.
    Parkinsonism & Related Disorders 09/2015; DOI:10.1016/j.parkreldis.2015.09.007 · 3.97 Impact Factor
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    • "There continues to be substantial interest in models that overexpress the protein alpha-synuclein (α-syn) to model parkinsonism. A large body of evidence points to α-syn’s involvement in PD, including the fact that point mutations and multiplications of the SNCA gene have been linked to onset of familial forms of PD [1-3]. Subsequent discoveries of the presence of α-syn in the hallmark protein aggregations (Lewy Bodies) and dystrophic neurites of PD have linked α-syn to sporadic forms of the disease [4,5]. "
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    ABSTRACT: The discovery of the involvement of alpha-synuclein (α-syn) in Parkinson's disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated α-syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype α-syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 10(13)) or varying titers (2.2 x 10(12), 1.0 x 10(13), 5.9 x 10(13), or 1.0 x 10(14)) of rAAV2/5-α-syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 10(14) titer rAAV2/5-α-syn injection and 8 weeks following 1.0 x 10(13) titer rAAV2/5-α-syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 10(13) and 1.0 x 10(14) rAAV2/5-α-syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of α-syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 10(13) rAAV2/5-α-syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5-α-syn overexpression model demonstrates robust nigrostriatal α-syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.
    PLoS ONE 11/2013; 8(11):e81426. DOI:10.1371/journal.pone.0081426 · 3.23 Impact Factor
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    • "Three SNCA missense mutations have been reported in pedigrees with autosomal dominant inheritance.3–5 We recently identified the c.150T>G/p.H50Q mutation in DNA derived from the brain of a single apparently sporadic case of late-onset PD.6 Copy number variations (CNVs, duplications and triplications) have also been described,7,8 and noncoding variation in SNCA is a risk factor for sporadic PD.9 Several large studies analyzing DNA from blood lymphocytes have not found additional mutations, including 1 of more than 1900 mostly sporadic patients.10 "
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    ABSTRACT: Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 Movement Disorder Society.
    Movement Disorders 06/2013; 28(6). DOI:10.1002/mds.25502 · 5.68 Impact Factor
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