Case-Control Study of the Parkin Gene in Early-Onset Parkinson Disease

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
JAMA Neurology (Impact Factor: 7.42). 04/2006; 63(4):548-52. DOI: 10.1001/archneur.63.4.548
Source: PubMed


Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls.
To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged < or =50 years) and controls participating in a familial aggregation study.
We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction.
Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations.
The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.

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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.
    Journal of Clinical Neurology 07/2014; 10(3):244-8. DOI:10.3988/jcn.2014.10.3.244 · 1.70 Impact Factor
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    • "While most PD cases are sporadic, about 10% of the cases have pathogenic mutations in the individual genes including alpha-synuclein, Leucine-Rich Repeat Kinase 2 (LRRK2), parkin, DJ-1, and PTEN-induced putative kinase 1 (PINK1) 7-13. Intriguingly, some PD patients carry mutation only in the one allele of the recessive genes parkin and PINK1 and some people carrying mutation in the dominant gene LRRK2 do not develop PD in their lives 14-16. The penetrance and expressivity of PD phenotypes appears to be determined not only by pathogenic mutation in the identified genes, but also by undefined factors. "
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    ABSTRACT: Environmental exposure, genetic modification, and aging are considered risky for Parkinson's disease (PD). How these risk factors cooperate to induce progressive neurodegeneration in PD remains largely unknown. Paraquat is an herbicide commonly used for weed and grass control. Exposure to paraquat is associated with the increased incidence of PD. In contrast to familial PD, most sporadic PD cases do not have genetic mutation, but may suffer from partial dysfunction of neuron-protective genes as aging. Using conditional transgenic RNAi, we showed that temporal silencing of PINK1 expression in adult mice increased striatal dopamine, the phenotype that could not be induced by constitutive gene silencing. Moreover, early exposure to paraquat sensitized dopaminergic neurons to subsequent silencing of PINK1 gene expression, leading to a significant loss of dopaminergic neurons. Our findings suggest a novel pathogenesis of PD: exposure to environmental toxicants early in the life reduces the threshold of developing PD and partial dysfunction of neuron-protective genes later in the life initiates a process of progressive neurodegeneration to cross the reduced threshold of disease onset.
    International journal of biological sciences 10/2011; 7(8):1180-7. · 4.51 Impact Factor
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    • "Molecular genetic analyses—We have previously described the methods used to detect mutations in the parkin gene in the 247 cases recruited in GEPD (Wang et al., 2008). In CORE-PD, we screened 709 samples obtained from PD probands for point mutations using denaturing high performance liquid chromatography and a parkin genotyping array (Clark et al., 2007) and for copy number variation (exon deletions and duplications) using semiquantitative multiplex polymerase chain reaction (Clark et al., 2006). The genotyping array was used to analyze amplicons in DNA samples with abnormal elution profiles and has excellent sensitivity and specificity for detection of sequence variants when compared to the gold standard of sequencing (Clark et al., 2007). "
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    ABSTRACT: The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.
    Journal of the International Neuropsychological Society 01/2011; 17(1):91-100. DOI:10.1017/S1355617710001190 · 2.96 Impact Factor
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