Genetic analysis of Parkin in early onset Parkinson's disease (PD): Novel intron 9 g > a single nucleotide polymorphism and risk of Taiwanese PD

Abstract

Early onset Parkinson's disease (PD) has been associated with mutations in Parkin. We screened Parkin mutations in a cohort of Taiwanese early onset PD using direct cDNA sequencing. Two deletions (Ex2-3del and Ex5del), one point mutation (R334C), one 86-bp IVS9 insertion (c.1084intron(+)), and two polymorphisms (S167N and V380L) were identified. The mutations identified are heterozygous and none of the mutation carriers possess two Parkin mutations. The c.1084intron(+) was due to a novel IVS9 g > a change. To assess the association of IVS9 g > a, S167N and V380L with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. Although the difference is not significant, the V380L C allele frequency was notably lower in PD patients than the controls and a trend toward decrease in risk of developing PD was evident (odds ratio: 0.71, 95% confidence interval: 0.53-0.97, P = 0.029). Contrarily the IVS9 g > a a allele frequency was notably higher in PD patients than the controls and a trend toward increase in risk of developing PD was also evident (odds ratio: 1.65, 95% confidence interval: 1.06-2.59, P = 0.028). Quantitative real-time PCR showed that the relative Parkin c.1084intron(+) mRNA expression was increased in PD patients with IVS9 ga genotype as compared to gg genotype. Pairwise genotype analysis revealed that IVS9 gg genotype strengthens the negative association of the V380L GC genotype with PD (odds ratio: 0.67, 95% confidence interval: 0.48-0.94, P = 0.021). The results of Parkin mutation/polymorphism screening may contribute to our understanding of PD.

P268S in NOD2 associates with susceptibility to Parkinson’s disease in Chinese population

“…12.7% PD patients and 7.9% controls carried the heterozygous IVS9 mutation, but the allele difference and genotype difference were not statistically significant. This result is consistent with the results of a previous study of 506 patients and 508 controls in Taiwan [18]. Further investigation into the association between IVS9G > A and PD need, through larger sample size from various populations.…”

“…Exon deletion, insertion, and point mutations in PARK2 have been found in different ethnic groups [17]. In 2009, Yih-Ru Wu screened 506 Taiwan sporadic patients with age of onset below 50 years for PARK2 gene mutation and identified a novel IVS9 insertion (c.1084intron + ) [18]. The c.1084intron + was due to a G > A polymorphism at position −6 of a cryptic splice acceptor site within IVS9.…”

FBXO7 Y52C Polymorphism as a Potential Protective Factor in Parkinson's Disease

“…The mean age at onset (AAO) of PD was 62.0±11.5 years, ranging between 19 and 93 years. For juvenile PD patients (AAO≤50), mutations in the Parkin , PINK1 , DJ-1, ATP13A2 and G2019S LRRK2 were excluded ([25], [26], [27] and unpublished results). A group of 516 normal controls without neurodegenerative diseases were recruited from the same ethnic community.…”

The Impact of Mitochondrial DNA and Nuclear Genes Related to Mitochondrial Functioning on the Risk of Parkinson’s Disease

“…Earlier reports showed either no association for V380L or pointed to the G/G V380L genotype as increasing the PD risk and/or allel C decreasing it [222, 223]. Among PD patients potentially exposed to pesticides (postulated to increase PD risk) those carrying allele C of V380L had a higher age at onset [224].…”