Expanding the clinical phenotype of <i>SNCA</i> duplication carriers

Nishioka, Kenya; Ross, Owen A.; Ishii, Kenji; Kachergus, Jennifer M.; Ishiwata, Kiichi; Kitagawa, Mayumi; Kono, Satoshi; Obi, Tomokazu; Mizoguchi, Koichi; Inoue, Yuichi; Imai, Hisao; Takanashi, Masashi; Mizuno, Yoshikuni; Farrer, Matthew J.; Hattori, Nobutaka

doi:10.1002/mds.22682

Cited by 129 publications

(111 citation statements)

References 33 publications

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“…reported with negative phenotypes for motor symptoms, olfaction, and rapid eye movement sleep behavior (3,4). Here, we show, in this rare nonelderly sample, that carriers display reward learning deficits that may precede the development of clinical motor symptoms, providing a unique opportunity to further explore the nature of the premotor stage of Parkinson disease and to develop early biomarkers.…”

Section: Discussionmentioning

confidence: 70%

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α-Synuclein gene duplication impairs reward learning

Kéri

Moustafa

Myers

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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α-Synuclein (SNCA) plays an important role in the regulation of dopaminergic neurotransmission and neurodegeneration in Parkinson disease. We investigated reward and punishment learning in asymptomatic carriers of a rare SNCA gene duplication who were healthy siblings of patients with Parkinson disease. Results revealed that healthy SNCA duplication carriers displayed impaired reward and intact punishment learning compared with noncarriers. These results demonstrate that a copy number variation of the SNCA gene is associated with selective impairments on reinforcement learning in asymptomatic carriers without the motor symptoms of Parkinson disease.Parkinson disease | reinforcement learning | dopamine | basal ganglia I t has been demonstrated that the copy number variation of the α-synuclein gene (SNCA), which encodes a protein regulating dopamine turnover in the presynaptic terminal, causes Parkinson disease (1). The multiplication of the SNCA locus is very rare; beyond the few families reported in the literature (2), Ahn et al. (3) identified three patients with duplication from 1,106 screened individuals with parkinsonism. Each patient had biological relatives who were asymptomatic carriers. However, the penetrance of SNCA duplication is not exactly defined, and its behavioral consequences in asymptomatic carriers are unknown (4).The protein encoded by the SNCA gene may serve as a regulator of the mesolimbic dopaminergic system and hence might play an important role in reward learning. Oksman et al. (5) showed that the absence of SNCA resulting from a spontaneous mutation in C57BL/6J mice enhanced operant behavior during intracranial self-stimulation, suggesting that the lack of SNCA sensitized the reward system of the brain. Transgenic mice overexpressing A30P-mutated SNCA exhibit reduced locomotor activity and smaller evoked dopamine release in the striatum (6). Evidence from a positron emission tomography study in humans suggests that high dopamine synthesis in the striatum results in better reversal learning from reward than from punishment, whereas low baseline dopamine synthesis is associated with the opposite pattern of performance (7).In this study, we aimed to investigate the possible reinforcement learning phenotype of SNCA multiplication and overexpression in humans. We assessed seven asymptomatic healthy carriers of SNCA duplication who later developed Parkinson disease and 10 noncarrier comparison participants on a reward-and punishmentguided A/B probabilistic classification learning task. Participants could win or lose imaginary quarter dollars by deciding whether abstract images belong to category A or B (Fig. 1A). On reward trials, correct responses were followed by a 25-point gain. On punishment trials, incorrect responses were followed by a 25-point loss. Some images belonged to category A with 80% probability and to category B with 20% probability, whereas others had the opposite category probability. On some trials, feedback was not provided. Reward learning was also assessed with an ind...

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Section: Discussionmentioning

confidence: 70%

“…Each patient had biological relatives who were asymptomatic carriers. However, the penetrance of SNCA duplication is not exactly defined, and its behavioral consequences in asymptomatic carriers are unknown (4).…”

mentioning

confidence: 99%

α-Synuclein gene duplication impairs reward learning

Kéri

Moustafa

Myers

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…PD families with members carrying four copies of SNCA gene have been detected in South Africa, Iran, Japan, Pakistan and Italy [35][36][37][38][39][40]: in general, triplication generates very high expression of mRNA and protein and influences the clinical manifestations of PD, causing severe forms of Parkinsonism similar to dementia with Lewy body. Duplications have been reported in more numerous families than triplications [33,38,[41][42][43][44][45][46][47][48][49][50][51]. In some of the patients with the same ethnic background (Japan), haplotype analysis revealed their derivation from common founders [43,44].…”

Section: Sncamentioning

confidence: 99%

“…Duplications have been reported in more numerous families than triplications [33,38,[41][42][43][44][45][46][47][48][49][50][51]. In some of the patients with the same ethnic background (Japan), haplotype analysis revealed their derivation from common founders [43,44]. In contrast to triplication carriers, the clinical phenotype of patients with duplicated SNCA resembles idiopathic PD, mainly with late age at onset, good efficacy for levodopa therapy, slower disease progression and without early development of dementia.…”

Section: Sncamentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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“…At the same time, the overlap of pathophysiological events among clinically different neurogenetic diseases is also increasingly recognized, originating a sheer complexity of genotype-phenotype relationships. Abundant examples can be found in neurology where a given gene has been associated with different clinical presentations, even within the same family [Ito, 2012;Nishioka et al, 2009]. Furthermore, often the diverse clinical profiles also reflect variability that can be demonstrated in the neurophysiologic and pathologic examination even in patients with the same mutation [Muelas et al, 2010].…”

Section: Challenges For Neurogenetic Databasesmentioning

confidence: 99%

Databases for neurogenetics: Introduction, overview, and challenges

et al. 2012

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ABSTRACT:The importance for research and clinical utility of mutation databases, as well as the issues and difficulties entailed in their construction, is discussed within the Human Variome Project. While general principles and standards can apply to most human diseases, some specific questions arise when dealing with the nature of genetic neurological disorders. So far, publically accessible mutation databases exist for only about half of the genes causing neurogenetic disorders; and a considerable work is clearly still needed to optimize their content. The current landscape, main challenges, some potential solutions, and future perspectives on genetic databases for disorders of the nervous system are reviewed in this special issue of Human Mutation on neurogenetics.

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Expanding the clinical phenotype of SNCA duplication carriers

Cited by 129 publications

References 33 publications

α-Synuclein gene duplication impairs reward learning

α-Synuclein gene duplication impairs reward learning

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Databases for neurogenetics: Introduction, overview, and challenges

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