Investigations on the Point Mutations at nt 5460 of the mtDNA in Different Neurodegenerative and Neuromuscular Diseases

Abstract

Point mutations of the mitochondrial genome are often considered to be the cause of certain neurodegenerative disorders and mitochondrial myopathies. Recently, there has been a report on Alzheimer’s disease (AD) point mutations at position 5460 of the mitochondrial genome located within the ND2 gene. Using allele-specific PCR with a sensitivity of detection of less than 1% mutated mtDNA, we investigated postmortem brain samples from 48 patients with AD and blood samples of 15 patients with clinically diagnosed AD. In addition, we investigated tissue samples of patients with different neuromuscular disorders and patients with Downs syndrome. Independent of the tissue analysed very few of all the tested samples of patients showed a point mutation at nt 5460 with a base substitution from G to A. Two out of 19 brain and 48 blood samples from controls carried this mutation. The G to T transversion was not found in any of the so far tested samples. Our results do not support the previously reported significant high frequency of these mutations in AD. A polymorphism seems more likely.

Mitochondrial DNA polymorphisms in pathologically proven Parkinson’s disease

“…Whilst both the A4336G and the G5460A polymorphism are present in both patients and controls, virtually all pathogenic mutations of the mitochondrial DNA are found only in patients and their relatives, but not in normal control populations [6]. Finally, heteroplasmy, regarded as a cardinal feature of pathogenic mutations of the mitochondrial DNA [7], is only present in some patients and some controls with the G5460A polymorphism [10], whereas all the other mitochondrial DNA sequence changes described in Caucasian patients with PD are homoplasmic ([24, 26]; own observations).…”

The other, forgotten genome: mitochondrial DNA and mental disorders

“…Although several mtDNA mutations/polymorphisms, such as 5460A, 19 4336C, [20][21][22] and 3397G, 20 have been associated with Alzheimer's disease, these findings have not been replicated by later studies. [23][24][25][26][27][28] And although heteroplasmic mutations were found in platelets from patients with Alzheimer's disease, 29 this was later found to be an artifact produced by pseudogenes from the nuclear genome. [30][31][32] Although increased levels of deletion in brains postmortem were reported, again this was not confirmed in subsequent studies.…”

Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly

“…Individual mtDNA mutations have been identified in patients with AD [45, 70–84]. However, these studies were small and most of the identified variants have not been confirmed [77, 79–84].…”

“…However, these studies were small and most of the identified variants have not been confirmed [77, 79–84]. In the present study, we first set out to assess the role of common mtDNA haplogroups and individual variants in dementia risk and longitudinal cognitive change among 1,631 participants from the population-based Health, Aging, and Body Composition (Health ABC) Study.…”