Abstract
BackgroundMitochondrial DNA polymerase gamma (POLG1) mutations were associated with levodopa-responsive Parkinsonism. POLG1 gene contains a number of common nonsynonymous SNPs and intronic regulatory SNPs which may have functional consequences. It is of great interest to discover polymorphisms variants associated with Parkinson's disease (PD), both in isolation and in combination with specific SNPs.Materials and MethodsWe conducted a case-control study and genotyped twenty SNPs and poly-Q polymorphisms of POLG1 gene including in 344 Chinese sporadic PD patients and 154 healthy controls. All the polymorphisms of POLG1 we found in this study were sequenced by PCR products with dye terminator methods using an ABI-3100 sequencer. Hardy-Weinberg equilibrium and linkage disequilibrium (LD) for association between twenty POLG1 SNPs and PD were calculated using the program Haploview.Principal ResultsWe provided evidence for strong association of four intronic SNPs of the POLG1 gene (new report: c.2070-12T>A and rs2307439: c.2070-64G>A in intron 11, P = 0.00011, OR = 1.727; rs2302084: c.3105-11T>C and rs2246900: c.3105-36A>G in intron 19, P = 0.00031, OR = 1.648) with PD. However, we did not identify any significant association between ten exonic SNPs of POLG1 and PD. Linkage disequilibrium analysis indicated that c.2070-12T>A and c.2070-64G>A could be parsed into one block as Haplotype 1 as well as c.3105-11T>C and c.3105-36A>G in Haplotype 2. In addition, case and control study on association of POLG1 CAG repeat (poly-Q) alleles with PD showed a significant association (P = 0.03, OR = 2.16) of the non-10/11Q variants with PD. Although intronic SNPs associated with PD didn't influence POLG1 mRNA alternative splicing, there was a strong association of c.2070-12T>A and c.2070-64G>A with decreased POLG1 mRNA level and protein levels.ConclusionsOur findings indicate that POLG1 may play a role in the pathogenesis of PD in Chinese populations.
Highlights
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders caused by loss of dopaminergic neurons in the substantia nigra [1]. 5–10% of PD cases begin at onset of the ages between 20 and 50, which is classified as young onset [2]
Our findings indicate that POLG1 may play a role in the pathogenesis of PD in Chinese populations
POLG1 exonic and intronic SNP screening By direct DNA sequencing in twenty-five individuals, we identified twenty SNPs within the POLG1 gene, including ten exonic SNPs and ten intronic SNPs
Summary
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders caused by loss of dopaminergic neurons in the substantia nigra [1]. 5–10% of PD cases begin at onset of the ages between 20 and 50, which is classified as young onset [2]. Accumulation of somatic mitochondrial DNA (mtDNA) deletions was observed in the substantia nigra in PD and several gene products of familial Parkinsonism, e.g., mitochondrial DNA polymerase gamma gene (POLG1), had a connection to mitochondrial function [2,5,7]. Mitochondrial DNA primary genetic abnormalities or secondary rearrangements due to POLG1 gene mutation could directly cause Parkinsonism [5,9]. Two missense mutations in POLG1, G737R and R853W, were reported in a family with early onset Parkinsonism [13] Another W748S missense mutation was found in a Finnish patient with a mixed disease background of Parkinsonism, chronic progressive external ophthalmoplegia, and peripheral neuropathy [14]. Increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) was found in Finnish idiopathic apparently sporadic PD patients, but conflicting reports exist. Mitochondrial DNA polymerase gamma (POLG1) mutations were associated with levodopa-responsive Parkinsonism. It is of great interest to discover polymorphisms variants associated with Parkinson’s disease (PD), both in isolation and in combination with specific SNPs
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