Parkinson Study Group-PROGENI Investigators.Parkinson Study Group-PROGENI Investigators Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations.

Medical and Molecular Genetics, Indiana University, School of Medicine, Hereditary Genomics Division, 410 W. 10th St., MI-4000, Indianapolis, IN 46202, USA.
Neurology (Impact Factor: 8.29). 07/2009; 73(4):279-86. DOI: 10.1212/WNL.0b013e3181af7a33
Source: PubMed


Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD.
We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations.
We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at < or =45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at < or =45 years, p = 0.06).
Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.

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    • "Heterozygous PARK2 gene-dosage mutations in PD have been reported worldwide.3,4,5,6,7,9,15,16,17,21,28 However, whether heterozygous mutations of PARK2 are genetic risk factors for PD remains a matter of controversy, even though some studies performed PARK2 genotyping in control populations.14,15,16,17,18,19,20 Since most of the subjects who participated in these studies were not Asian, we cannot directly compare our results with those of these other studies. "
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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. Methods 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. Results 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. Conclusions Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.
    Full-text · Article · Jul 2014 · Journal of Clinical Neurology
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    • "To this regard, a number of PARK2 cis-acting mutations identified in patients with Parkinson’s disease have been collected in Parkinson Disease Mutations database. To date, point mutations localized in splice acceptor or donor sites of PARK2 introns 1, 6, 7, 10, 12, 13 and 16 have been investigated [53-59], while cis-acting mutations in splice sites of exons 2-5, 8, 9, 11, 14, 15, 17 and in the other splicing regulatory regions have not yet been explored and need to be assessed. Moreover, deregulation of alternative splicing may be the result of changes in the components of spliceosome machinery (trans-acting mutations). "
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    ABSTRACT: The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome. This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer's disease. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells. This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this versatile form of genetic regulation may have pathological consequences.
    Full-text · Article · Jun 2014 · Current Genomics
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    • "We also identified the c.719C > T (p.T240M) substitution in one patient. This change had already been described, and it had been previously classified as a known pathogenic variant [18, 20]. Our in silico analysis corroborated these data and considered that this alteration affects the PARKIN function, being probably pathogenic. "
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    ABSTRACT: Parkinson's disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinson's disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5-10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinson's disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinson's disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide.
    Full-text · Article · Aug 2013 · Disease markers
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