Rare heterozygous Parkin variants in French early-onset Parkinson disease patients and controls
Mutations in the parkin gene cause autosomal recessive early-onset parkinsonism. The effect of single heterozygous mutations in parkin is still unclear. The aim of this study was to evaluate the frequency of exonic parkin variants in a case-control study.
The parkin gene was screened for both point mutations and exon rearrangements in 172 French patients with Parkinson disease (PD) and 170 controls from the same population. Patients with single parkin variants were also screened for PINK1, DJ-1 and LRRK2 exon 41 mutations.
10 exonic sequence variations were identified, including 3 known polymorphisms and 7 rare heterozygous variants, 2 of which were novel. There were significantly more rare heterozygous variants in patients (n = 10) with early-onset PD than in controls (n = 2). Screening of PINK1, DJ-1 and LRRK2 exon 41 in the 10 patients heterozygous for parkin failed to identify a second causative mutation.
These results suggest that single parkin mutations increase the risk of early-onset PD, but the possibility of a second parkin mutation cannot be excluded.
Available from: Min Kyung Chu
- "Although PARK2 mutations were initially found in patients with familial PD with an autosomal-recessive mode of inheritance, heterozygous mutations were also not uncommonly found in PD patients.1,2,3,12,13 Whether a single heterozygous mutation of PARK2 is a risk factor for PD is controversial.14,15,16,17,18,19,20 Pankratz et al.19 reported that PARK2 dosage mutation, rather than a point mutation or small insertion/deletion mutation, was a risk factor for familial PD, and may also be associated with a younger age at onset. "
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ABSTRACT: Background and Purpose
There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage mutation of PARK2, rather than a point mutation or small insertion/deletion mutation, was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations.
We performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested.
We identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls.
Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.
Available from: Yue Huang
- "Rare patients have missense mutations (A53T, A30P, and E46K) or multiplications of SNCA , but all PD patients accumulate phosphorylated α-synuclein in the form Lewy pathologies [4, 5]. Leucine-rich repeat kinase 2 (LRRK2) has been identified as the second and more common gene responsible for autosomal-dominant PD [6–9]. The function of the large LRRK2 protein remains unclear, although its serine–threonine/tyrosine kinase function is considered most important for PD aetiology due to the occurrence of the most common LRRK2 mutation (G2019S) in this domain . "
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ABSTRACT: Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson’s disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex. In disease-affected regions, we show co-localization of these two proteins in neurons and Lewy body inclusions. Further, in vitro experiments show a molecular interaction between α-synuclein and LRRK2 under endogenous and over-expression conditions. In a cell culture model of α-synuclein inclusion formation, LRRK2 co-localizes with the α-synuclein inclusions, and knocking down LRRK2 increases the number of smaller inclusions. In addition to providing strong evidence for an interaction between LRRK2 and α-synuclein, our results shed light on the complex relationship between these two proteins in the brains of patients with PD and the underlying molecular mechanisms of the disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-012-0984-y) contains supplementary material, which is available to authorized users.
Available from: Braxton D Mitchell
- "Various studies of complex diseases indicate that young onset disease is more likely due to multiple rare exonic variants with large effects as compared to late-onset disease. As an example, studies identified rare mutations in the parkin gene in the PARK2 locus that cause sporadic early-onset parkinsonism . Subsequently, other studies identified other parkin variants that play a role in the common late-onset forms of Parkinson disease (age of onset >45 years) . "
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ABSTRACT: The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.
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