A novel screen for nuclear mitochondrial gene associations with Parkinson?s disease (original) (raw)
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Journal of Human Genetics, 2008
Mitochondrial complex I deficiency has been implicated in the pathogenesis of Parkinson's disease (PD), but as yet no mitochondrial DNA (mtDNA) variations have been identified that could account for the impaired complex I activity. On the other hand, it has been suggested that mtDNA polymorphisms (mtSNPs) or haplogroups may modify the risk of developing PD. Here, we determined the distributions of ten mtSNPs that define the nine major European haplogroups among 224 PD patients and 383 controls from Crete, an island of 0.6 million inhabitants who share a similar genetic background and a common environment. The recruitment of patients and controls was restricted to individuals of Cretan origin for at least three generations from both parental sides in order to avoid population admixture and subsequent genetic heterogeneity. We found no mtSNP or mtDNA haplogroup that predisposes to PD, although there was a trend for haplogroups J, T, U and I and the supercluster of haplogroups UKJT to be slightly underrepresented in our PD patients as compared to controls. While a combination of common mtSNPs (present in C5% of the general population) may decrease the chance of developing PD, this effect was minor in the Cretan population.
Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease
The American Journal of Human Genetics, 2003
Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; ) or K (OR 0.52; 95% CI 0.30-0.90; ) demonstrated a significant decrease in risk of P p .02 P p .02 PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P p ). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH .0001 dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71;
Genotyping Parkinson Disease-Associated Mitochondrial Polymorphisms
Clinical Medicine & Research, 2004
The purpose of this study was to establish a system for rapidly detecting single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) using hybridization probes and melting temperature (Tm) analysis. This technology should prove useful for population-based studies on the interaction between genetic factors and environmental exposures and the risk of Parkinson disease (PD). METHODS Mitochondrial DNA (mtDNA) was extracted from whole blood. Rapid polymerase chain reaction (PCR) and melting curve analyses were performed with primers and fluorochrome-labeled probes on a LightCycler (Roche Molecular Biochemical, Mannheim, Germany). Genotyping of 10 SNPs in 15 subjects was based on the analysis of allele-specific Tm of detection probes. The results of melting curve analyses were verified by sequencing all 150 PCR products. RESULTS Real-time monitoring showed optimal PCR amplification of each mtDNA fragment. The nucleotide changes at positions 1719,
Mitochondrial DNA polymorphisms and risk of Parkinson's disease in Spanish population
Journal of The Neurological Sciences, 2005
A critical role of mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). The association of mitochondrial DNA (mtDNA) polymorphisms 9055G=A, 10398G=A and 13708G=A with PD has been controversial. In this study we analyzed whether these three genetic polymorphisms are associated with PD in a cohort of 416 PD cases and 372 ethnically matched controls. The allele frequency distribution of any of these three analyzed polymorphisms was not significantly different between the cases and the controls. None of the six haplotypes derived influences risk of PD. Notably, after stratification by age, individuals over 70 years of age carrying the haplotype 9055G-10398A-13708G demonstrated a significant decrease in risk of developing PD (OR ¼ 0.44, 95% CI ¼ 0.24-0.80, p ¼ 0.008). These results suggest that the mtDNA haplotype 9055G-10398A-13708G plays a role in PD susceptibility among Taiwanese people older than 70 years of age.
Parkinson's disease and mitochondrial gene variations: A review
Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochon-drial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD.
Sequence Analysis of the Entire Mitochondrial Genome in Parkinson's Disease
Biochemical and Biophysical Research Communications, 2002
The pathogenesis of Parkinson's disease (PD) is largely unknown. Indirect evidence suggests that mutations in mitochondrial DNA (mtDNA) might play a role, but previous studies have not consistently associated any specific mutations with PD. However, these studies have generally been confined to limited areas of the mitochondrial genome. We therefore sequenced the entire mitochondrial genome from substantia nigra of 8 PD and 9 control subjects. Several sequence variants were distributed differently between PD and control subjects, but all were previously reported polymorphisms. Several secondary LHON mutations were found, as well as a number of novel missense mutations, but all were rare and did not differ between PD and control subjects. Finally, PD and control subjects did not differ in the total number of all mutations, nor the total number of missense mutations. Thus, mtDNA involvement in PD, if any, is likely to be complex and should be reconsidered carefully. © 2002 Elsevier Science (USA)
Mitochondrial DNA analysis in Parkinson's disease
Movement Disorders, 1990
The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-Cphenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples. RE. Inhibition of NADHlinked oxidation in brain mitochondria by MPP', a metabolite of the neurotoxin MPTP. Life Sci 1985;36:2503-2508. Denton T, Howard BD. A dopaminergic cell line variant resistant to the neurotoxin MPTP. J Neurochern 1987;49: 622-630. Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial Complex I deficiency in Parkinson's disease. Lancet 1989;l: 1269. Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondria1 Complex I deficiency in Parkinson's disease. J Neurochem 1990;54:823-827. Chomyn A, Mariottini P, Cleeter MJW, Ragan CI, Doolittle RF, Yagi MA, Hatefi Y, Attardi G. Functional assignment of the unidentified reading frames of human mitochondrial DNA. In: Quagliariello E, Slater EC, Palmieri F, Saccone C, Kroon AM, eds. Achievements and perspectives in mitochondrial research, volume ii. Amsterdam: Elsevier Science Publishers, 1987: 259-275. Holt IJ, Harding AE, Morgan-Hughes J. Deletions of mitochondrial DNA in patients with mitochondrial myopathy. Nature 1988;33 1 :717-719. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J A401 Bioll975; Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983;132:613. 98503-517.
Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians
European Journal of Human Genetics, 2005
It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinson's disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (450, o65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in 450year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.
Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease
Neurology, 2000
To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. Background: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. Methods: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. Results: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. Conclusions: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.