A comprehensive analysis of deletions, multiplications, and copy number variations in
            <i>PARK2</i>

Kay, Denise M.; Stevens, Colleen F.; Hamza, Taye H.; Montimurro, Jennifer S.; Zabetian, Cyrus P.; Factor, Stewart A.; Samii, Ali; Griffith, Alida; Roberts, John W.; Molho, Eric; Higgins, Donald S.; Gancher, S.; Moses, Lina M.; Zareparsi, Sepideh; Poorkaj, Parvonah; Bird, T.; Nutt, John G.; Schellenberg, Gerard D.; Payami, Haydeh

doi:10.1212/wnl.0b013e3181f4d832

Cited by 85 publications

(90 citation statements)

References 31 publications

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“…We identified a heterozygous deletion in exon 4 of PARKIN gene in one patient who has a juvenile AAO of 12 years and no family history of the disease. This alteration had already been reported by other groups in PD patients and healthy individuals [3,6,15,22]. Kay and colleagues (2010) demonstrated that heterozygous dosage mutations in exons 2-4 are common and well-tolerated in control subjects [15].…”

Section: Discussionsupporting

confidence: 63%

Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

et al. 2012

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Abstract.Parkinson's disease is one of the most common neurodegenerative disorders associated with aging, reaching ∼ 2% of individuals over 65 years. Knowledge achieved in the last decade about the genetic basis of Parkinson's disease clearly shows that genetic factors play an important role in the etiology of this disorder. Exon dosage variations account for a high proportion of Parkinson's disease mutations, mainly for PARKIN gene. In the present study, we screened genomic rearrangements in SNCA, PARKIN, PINK1 and DJ-1 genes in 102 Brazilian Parkinson's disease patients with early onset (age of onset 50 years), using the multiplex ligation-dependent probe amplification method. Family history was reported by 24 patients, while 78 were sporadic cases. Screening of exon dosage revealed PARKIN and PINK1 copy number variations, but no dosage alteration was found in SNCA and DJ-1 genes. Most of the carriers harbor heterozygous deletions or duplications in the PARKIN gene and only one patient was found to have a deletion in PINK1 exon 1. Data about dosage changes are scarce in the Brazilian population, which stresses the importance of including exon dosage analysis in Parkinson's disease genetic studies.

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Section: Discussionsupporting

confidence: 63%

Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

et al. 2012

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“…For this reason, more than 200 putative pathogenic mutations have been reported worldwide, affecting numerous ethnic populations [33,35,59,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The PARK2 mutation spectrum includes homozygous or compound heterozygous missense and nonsense point mutations, as well as several exon rearrangements (both duplications and deletions) involving all 12 exons and the promoter region.…”

Section: Park2mentioning

confidence: 99%

“…Several studies have sought to address this issue, but the findings published so far are inconsistent and conflicting. Some reports indicate that CNVs heterozygous mutations in PARK2 associate with increased PD risk [49,68], albeit others found no differences for an association [33,69]. Not only association studies but also examinations of families have yielded contradictory results.…”

Section: Park2mentioning

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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“…Rare CNVs are important genetic causes of human diseases, especially neurological disorders including PD [26][27][28][29][30][31][32] .…”

Section: No Copy Number Variations Of the Cp Gene In Pd Patientsmentioning

confidence: 99%

“…The PARK2 gene is a molecular diagnostic test for parkinsonism. Kay et al reported that a total of 0.95% of controls and 0.86% of patients carry a heterozygous CNV mutation of the PARK2 gene [30] . Thus, there is no compelling evidence for an association of heterozygous pathological states in PD [33][34][35] .…”

Section: No Copy Number Variations Of the Cp Gene In Pd Patientsmentioning

confidence: 99%

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

et al. 2015

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Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson's disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/ iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were signifi cantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no signifi cant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

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A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

Cited by 85 publications

References 31 publications

Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

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

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

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