Mitochondrial DNA Variants Observed in Alzheimer Disease and Parkinson Disease Patients

Shoffner, John M.; Brown, Michael D.; Torroni, Antonio; Lott, Marie T.; Cabell, Margaret F.; Mirra, Suzanne S.; Beal, M. Flint; Yang, Chi Chuan; Gearing, Marla; Salvo, Rino; Watts, Ray L.; Juncos, Jorge L.; Hansen, Lawrence A.; Crain, Barbara J.; Fayad, M.; Reckord, Calvin L.; Wallace, Douglas C.

doi:10.1006/geno.1993.1299

Cited by 427 publications

(247 citation statements)

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“…[38][39][40] Certain mitochondrial polymorphisms, such as those at position 4917, are associated with late-onset neurodegenerative diseases and their relatively high frequency suggests that they do not severely affect reproductive fitness. [24][25][26][27][28] For this reason, there may have been relatively little selective pressure against these potentially deleterious polymorphisms. The present findings point the way for future studies to quantify the biochemical effects of the 4917G allele, especially as they relate to free radical generation.…”

Section: Discussionmentioning

confidence: 99%

“…Epidemiological evidence for functional differences among haplogroups has been demonstrated previously in studies of neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis. [24][25][26][27][28] We previously described an association between haplogroup T and NRTI-associated PN among HIV-infected US participants in a prospective, randomized clinical trial. 29 Mitochondrial haplogroup T is found primarily in people of European descent, hence our analyses focused on Caucasians.…”

Section: Introductionmentioning

confidence: 99%

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The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

et al. 2007

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Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (X grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR) ¼ 1.98 (95% confidence interval (CI) 1.05-3.75); P ¼ 0.04) and 4917G (OR ¼ 2.93 (95% CI 1.25-6.89); P ¼ 0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR ¼ 2.0 (95% CI 1.1-4.0) P ¼ 0.04) and 4917G (OR ¼ 5.5 (95% CI 1.6-18.7) Po0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

et al. 2007

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“…18,19 While some reports have suggested an increased frequency of certain mtDNA polymorphisms in PD, this has not been replicated in all studies. [20][21][22][23][24] Certain mtDNA haplotypes influence PD expression and haplotype J was associated with a significant decrease in risk for PD, which in turn is strongly associated with the presence of a single nucleotide polymorphism at A10398G. 25 A second showed a 22% decrease in PD in those with the UKJT haplotype cluster.…”

Section: Mitochondrial Dna Mutations In Pdmentioning

confidence: 99%

Mitochondrial dysfunction in Parkinson's disease

2007

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“…Therefore, every point mutation, or deletion, has the capacity to affect the mitochondrial function of cellular respiration support. MtDNA also lacks the protection of histones or DNA binding proteins (Shoffner et al, 1993) and is believed to have only a very basic repair mechanism (Croteau et al, 1999). Bohr and Dianov have reported that this mechanism can repair excision and bases caused by oxidative insult (Bohr and Dianov, 1999).…”

Section: Introductionmentioning

confidence: 99%

A comparison of mitochondrial and nuclear DNA status in testicular sperm from fertile men and those with obstructive azoospermia

O’Connell

McClure²,

Lewis

2002

Human Reproduction

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BACKGROUND: Mitochondria are vital to sperm as their motility powerhouses. They are also the only animal organelles with their own unique genome; encoding subunits for the complexes required for the electron transfer chain. METHODS: A modified long PCR technique was used to study mitochondrial DNA (mtDNA) in ejaculated and testicular sperm samples from fertile men undergoing vasectomy (n ⍧ 11) and testicular sperm from men with obstructive azoospermia (n ⍧ 25). Nuclear DNA (nDNA) fragmentation was measured by an alkaline gel electrophoresis (comet) assay. RESULTS: Wild-type mtDNA was detected in only 60% of fertile men's testicular sperm, 50% of their ejaculated sperm and 46% of testicular sperm from men with obstructive azoospermia. The incidence of mitochondrial deletions in testicular sperm of fertile and infertile men was not significantly different, but the mean size of the deletions was significantly less in testicular sperm from fertile men compared with men with obstructive azoospermia (P < 0.02). NDNA fragmentation in testicular sperm from fertile men and men with obstructive azoospermia was not significantly different. CONCLUSION: Multiple mtDNA deletions are common in testicular and ejaculated sperm from both fertile and infertile men. However, in males with obstructive azoospermia, the mtDNA deletions in testicular sperm are of a larger scale.Key words: human sperm/male infertility/mitochondrial and nuclear DNA/obstructive azoospermia/ROS

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Mitochondrial DNA Variants Observed in Alzheimer Disease and Parkinson Disease Patients

Cited by 427 publications

References 0 publications

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

Mitochondrial dysfunction in Parkinson's disease

A comparison of mitochondrial and nuclear DNA status in testicular sperm from fertile men and those with obstructive azoospermia

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