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At least 19 recordsLinked to original sources

PubMed2006

Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants.

Common mitochondrial DNA (mtDNA) haplotypes in humans and mice have been associated with various phenotypes, including learning performance and disease penetrance. Notably, no influence of mtDNA haplotype in cell respiration has been demonstrated. Here, using cell lines carrying four different common mouse mtDNA haplotypes in an identical nuclear background, we show that the similar level of respiration among the cell lines is only apparent and is a consequence of compensatory mechanisms triggered by different production of reactive oxygen species. We observe that the respiration capacity per molecule of mtDNA in cells with the NIH3T3 or NZB mtDNA is lower than in those with the C57BL/6J, CBA/J or BALB/cJ mtDNA. In addition, we have determined the genetic element underlying these differences. Our data provide insight into the molecular basis of the complex phenotypes associated with common mtDNA variants and anticipate a relevant contribution of mtDNA single nucleotide polymorphisms to phenotypic variability in humans.

Adaptation, Biological↗

PubMed2000

Mitochondrial DNA variants in inclusion body myositis.

Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimer's disease. The pathological similarities between inclusion body myositis and Alzheimer's disease prompted an analysis of the relationship between the reported mutations and sporadic inclusion body myositis. The 4336G variant was not significantly increased in patients with inclusion body myositis or Alzheimer's disease when compared to controls. None of the patients with inclusion body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with inclusion body myositis and Alzheimer's disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with inclusion body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in inclusion body myositis than in Alzheimer's disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of inclusion body myositis.

Adult↗

PubMed1993

Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients.

Mitochondrial DNA (mtDNA) variants associated with Alzheimer disease (AD) and Parkinson disease (PD) were sought by restriction endonuclease analysis in a cohort of 71 late-onset Caucasian patients. A tRNA(Gln) gene variant at nucleotide pair (np) 4336 that altered a moderately conserved nucleotide was present in 9/173 (5.2%) of the patients surveyed but in only 0.7% of the general Caucasian controls. One of these patients harbored an additional novel 12S rRNA 5-nucleotide insertion at np 956-965, while a second had a missense variant at np 3397 that converted a highly conserved methionine to a valine. This latter mutation was also found in an independent AD + PD patient, as was a heteroplasmic 16S rRNA variant at np 3196. Additional studies will be required to determine the significance, if any, of these mutations.

Aged↗

PubMed1998

A common mitochondrial DNA variant is associated with insulin resistance in adult life.

Mitochondrial DNA is maternally inherited. Mitochondrial DNA mutations could contribute to the excess of maternal over paternal inheritance of non-insulin-dependent diabetes mellitus (NIDDM). We therefore investigated the relationship between this variant, insulin resistance and other risk factors in a cohort which had been well characterised with respect to diabetes. Blood DNA was screened from 251 men born in Hertfordshire 1920-1930 in whom an earlier cohort study had shown that glucose tolerance was inversely related to birthweight. The 16189 variant (T--> C transition) in the first hypervariable region of mitochondrial DNA was detected using the polymerase chain reaction and restriction digestion. DNA analysis showed that 28 of the 251 men (11%) had the 16189 variant. The prevalence of the 16189 variant increased progressively with fasting insulin concentration (p < 0.01). The association was independent of age and body mass index and was present after exclusion of the patients with NIDDM or impaired glucose tolerance. We found that insulin resistance in adult life was associated with the 16189 variant. This study provides the first evidence that a frequent mitochondrial variant may contribute to the phenotype in patients with a common multifactorial disorder.

Adult↗

PubMed2026

An immune-associated mitochondrial DNA variant with sex differences reveals a putative novel microprotein called MASL.

The use of mitochondrial wide association studies (MiWAS) to link mitochondrial DNA variants (mtSNPs) to phenotypes of interest has uncovered important connections between mitochondrial genes and human health. The recent introduction of a re-annotated mitochondrial genome that accounts for small open reading frames (sORFs) with protein coding potential suggests the existence of mitochondrial-derived microproteins, many of which remain uncharacterized. Thus, considering the re-annotated mitochondrial genome when conducting genomic analyses such as MiWAS facilitates the mapping of mtSNPs back to microprotein-encoding sORFs and uncovers interactions between mitochondrial microproteins and biological systems. Here, we employ MiWAS of venous blood samples from the Health and Retirement Study (HRS) and identify a mtSNP associated with sex-specific changes to immune composition. After accounting for re-annotation, we map the identified mtSNP back to a sORF that encodes a novel microprotein, termed MASL (Mitochondrial Associated Small d-Loop peptide). Complementary phenome-wide association studies (PheWAS) in HRS and and UK Biobank confirm interactions between this mtSNP and immune phenotypes of interest, and our targeted RNA-Seq method (mitoSNP-seq) elucidates sex-differences in gene expression and functional pathways potentially altered by this mtSNP that may be relevant to the associated microprotein. Early characterization of the MASL microprotein shows sex-differences in circulating MASL levels in human plasma, and sex-specific interactions when comparing male and female mice treated with synthesized MASL. Together, the results of this study not only contribute to our understanding of mitochondrial dynamics in immunity, but also provide early characterization of a novel mitochondrial-derived microprotein with sex-specific modulatory effects.

Genomics↗

PubMed1998

Update of MmtDB: a Metazoa mitochondrial DNA variants database.

The present paper describes the improvements in MmtDB, a specialised database designed to collect Metazoa mitochondrial DNA variants. Priority in the data collection has been given to Metazoa for which a large amount of variants is available, e.g., for humans. Starting from the sequences available in the Nucleotide Sequence Databases, the redundant sequences have been removed and new sequences from other sources have been added. Value-added information is associated to each variant sequence, e.g., analysed region, experimental method, tissue and cell lines, population data, sex, age, family code and information about the variation events (nucleotide position, involved gene, restriction site gain or loss). Cross-references are introduced to the EMBL Data Library, as well as an internal cross-referencing among MmtDB entries according to tissual, heteroplasmic, familiar and aplotypical correlation. Furthermore MmtDB has a new section, AMmtDB: Aligned Metazoan mitochondrial biosequences. MmtDB can be accessed through the World Wide Web at URL http://WWW.ba.cnr.it/[symbol: see text]areamt08/MmtDBWWW.htm

Animals↗

PubMed1997

MmtDB: a Metazoa mitochondrial DNA variants database.

The present paper describes the structure of MmtDB-a specialized database designed to collect Metazoa mitochondrial DNA variants. Priority in the data collection is given to the Metazoa species for which a large amount of variants is available, as it is the case for human variants. Starting from the sequences available in the Nucleotide Sequence Databases, the redundant sequences are removed and new sequences from other sources are added. Value-added information are associated to each variant sequence, e.g. analysed region, experimental method, tissue and cell lines, population data, sex, age, family code and information about the variation events (nucleotide position, involved gene, restriction site's gain or loss). Cross-references are introduced to the EMBL Data Library, as well as an internal cross-referencing among MmtDB entries according to their tissual, heteroplasmic, familiar and aplotypical correlation. MmtDB can be accessed through the World Wide Web at URL [see text].

Animals↗

PubMed1994

Nuclear background affects frequency dynamics of mitochondrial DNA variants in Drosophila simulans.

Transplasmic lines, in which the original mitochondrial DNA (mtDNA) had been completely replaced by the mtDNA of the donor, were constructed to test for selection on mtDNA variants and to investigate the effects of nuclear-cytoplasmic interactions in Drosophila simulans. These lines were used to set up 12 experimental populations putting in competition two mtDNA variants with two different starting frequencies. Population cages were maintained for 20 generations and periodically sampled to monitor haplotype frequencies. Evidence is provided for a complete reversal of the forces acting on the frequency dynamics of the mtDNA variants according to the lines used to establish the population cages. In the cages where the competing lines had both the original nuclear and mtDNA, the siII type mtDNA variant seemed to be favoured but the situation was reversed when this variant was put in a different nuclear background.

Animals↗

PubMed2000

Mitochondrial DNA variants in schizophrenia: association studies.

The frequency of three selected mitochondrial DNA variations was compared between cases with schizophrenia and two groups of unrelated controls: screened adults and neonates. The comparisons were conducted separately among Caucasians and African-Americans. No significant differences were detected, suggesting that the variants may not be associated with schizophrenia. Limitations of the study are discussed.

Adult↗

PubMed2004

Is cumulative frequency of mitochondrial DNA variants a biomarker for colorectal tumor progression?

To examine the relationship between mitochondrial DNA (mtDNA) alterations and colorectal tumorigenesis, we used high-resolution restriction endonucleases and sequencing to assess the mitochondrial genome from three histologic subtypes of colorectal adenomas (tubular = 8; tubulovillous = 9; and villous = 8), colorectal cancer (CRC) tissues = 27, and their matched surrounding normal tissue (MSNT) = 52. The mitochondrial genomes were amplified using 9 pairs of overlapping primers and systematically analyzed by means of high-resolution analysis. DNA fragments showing a shift in banding patterns between the three adenomas, CRC, in comparison to the MSNT were sequenced to identify the mtDNA alterations. A total of thirty-eight germ-line mtDNA variants were observed in this study. Twenty-two of the thirty-eight were identified as mutations and 59% (13 of 22) were silent mutations and one was a 1-bp insertion. Sixteen of thirty-eight were distinct SNPs in flanking regions of the restriction sites and, 6 of the 16 (37%) SNPs were not previously reported. Most of these mutations/SNPs were homoplasmic and distributed in various regions of mitochondrial genes including the 16S and 12S rRNA. Based on our results, mtDNA germline variants increased in prevalence with adenoma CRC progression. To the best of our knowledge, this is the first report to show an increased prevalence of mitochondrial gene variants in CRC tumorigenesis.

Aged↗

PubMed2003

A mitochondrial DNA variant associated with left ventricular hypertrophy in diabetes.

Diabetes was reported to be associated with a mitochondrial (mt) DNA mutation at 3243 and variants at 1310, 1438, 3290, 3316, 3394, 12,026, 15,927, and 16,189. Among these mtDNA abnormalities, those at 3243, 3316, 15,927, and 16,189 were also suggested to cause cardiomyopathies. We investigated the prevalence of such mtDNA abnormalities in 68 diabetic patients with LV hypertrophy (LVH), 100 without LVH, and 100 controls. Among the 9 mtDNA abnormalities, those at 3243, 3316, and 15,927 tended to be more prevalent in diabetic patients with LVH than in those without LVH (1%, 1%, and 4% vs. 0%, 0%, and 0%). Notably, the variant at 16,189 was more prevalent in diabetic patients with LVH than without LVH (46% vs. 24%, [Formula: see text] ). The odds ratio for LVH was 3.0 (95% CI, 1.5-6.1) for the 16,189 variant. A common mtDNA variant at 16,189 was found to be associated with LVH in diabetic patients.

DNA Mutational Analysis↗

PubMed2001

A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations.

Idiopathic dilated cardiomyopathy is a recognised manifestation of mitochondrial disease due to specific mitochondrial (mt) DNA mutations. However, whether mtDNA polymorphisms predispose to sporadic dilated cardiomyopathy is not known. We analysed two populations with this disorder for a general mtDNA variant (T16189C), previously implicated in susceptibility to type 2 diabetes. We noted an increased frequency of the polymorphism in both populations compared with controls (p=0.002). The polymorphism occurred on different mtDNA backgrounds, suggesting that it might be a functional variant. This association of an mtDNA variant with increased susceptibility to dilated cardiomyopathy provides evidence for a mitochondrial cause in sporadic disease.

Adolescent↗

PubMed2007

Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis.

The occurrence of multiple sclerosis (MS) in subjects clustering to a particular mitochondrial DNA (mtDNA) haplogroup/haplotype or carrying mtDNA mutations associated with Leber's hereditary optic neuropathy (LHON) has suggested that mitochondrial genome may contribute to susceptibility to MS. In the present study, 58 unrelated Bulgarian patients with relapsing remitting form of MS and 104 randomly selected healthy individuals were analysed for the presence of 14 mtDNA polymorphisms determining major European haplogroups as well as three (4216, 14 798, 13 708) secondary LHON mutations. Restriction enzyme analysis used to screen patients and controls for the common haplogroup-associated polymorphisms showed that each of these changes was present in MS patients at a similar frequency to control subjects. However, 21 of the 58 patients (36.2%) were positive for T4 216C mutation, while only 11.3% of the controls carried this secondary LHON base change (P < 0.01; OR = 4.38). Our finding indicated that 4216C base substitution could be considered as a predisposing marker for MS and supported the hypothesis that particular mtDNA variants could contribute to genetic susceptibility of MS, and merits further investigation.

Adult↗

PubMed1998

Novel Mitochondrial DNA Variant That May Give a False Positive Diagnosis for the T8993C Mutation.

Background: Two of the most common mutations in the mitochondrial DNA (mtDNA) of children occur at nucleotide 8993 (nt8993). The base substitutions of T to G (T8993G) and T to C (T8993C) are known to cause neurologic disorders and are routinely screened for in patients suspected of having a mitochondrial disorder. Methods and Results: Both mutations at nt8993 create a novel HpaII restriction endonuclease site and are usually detected by polymerase chain reaction (PCR) amplification of a section of the mtDNA containing nt8993, followed by HpaII digestion. The resulting fragment sizes are then analyzed by agarose gel electropho resis. Initial testing on a child referred for analysis suggested that the proband and his maternal relatives all had the common mtDNA mutation T8993C; however, subsequent restriction endonuclease and DNA sequencing analysis showed that the proband and his maternal relatives were homoplasmic for a novel variant at nt8856. This variant also creates an Hpa II restriction endonuclease site, and the fragments generated by the site are almost identical in size to those generated as a result of the nt8993 mutation when commonly used primers amplify the PCR product. Conclusions: A novel mutation in the mtDNA at nt8856 creates an HpaII restriction endonuclease site that has the potential to generate false positives when PCR products are tested for mutations at nt8993. This emphasizes the need for restriction endonuclease-based diagnostic tests for mtDNA mutations to account for the highly polymorphic nature of the mtDNA sequence and the importance of confirming a mutation by a second method.

Journal Article↗

PubMed2002

Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors.

In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.

Adenoma, Oxyphilic↗

PubMed1996

The tRNA(Gln) 4336 mitochondrial DNA variant is not a high penetrance mutation which predisposes to dementia before the age of 75 years.

The genetic factors that predispose to Alzheimer's disease (AD) are heterogeneous. Two recent reports have suggested that a mitochondrial DNA mutation within the tRNAGln gene, located at position 4336, may be a risk factor for AD, as it was found in 10/256 (3.9%) cases with AD confirmed by necropsy. Although low prevalences of this mutation were detected in non-demented subjects in both of these studies, the controls were not carefully matched with the AD cases. We have investigated the frequency of this mutation in two community based elderly cohorts in Cambridgeshire, who have participated in longitudinal studies of cognitive function. The 4336 mitochondrial mutation was detected in 8/ 443 people examined. These people were found to be non-demented at ages 74, 81, 84, 86, 89, 90, 91, and 102 years, in contrast to the previously described cases whose onset of dementia occurred between 60 and 76 years (mean 68). Accordingly, we believe that this mitochondrial variant is not a high penetrance mutation which predisposes to dementia before the age of 76 years.

Age of Onset↗

PubMed2006

A common mitochondrial DNA variant and increased body mass index as associated factors for development of type 2 diabetes: Additive effects of genetic and environmental factors.

OBJECTIVE: The suggested correlation between a T-to-C transition at the nucleotide 16189 in mitochondrial DNA (mtDNA) with increasing insulin resistance and adult-onset diabetes mellitus (DM) is debatable. METHODS: Our study examined mtDNA from 462 subjects with type 2 diabetes (T2DM) and 592 normoglycemic controls (non-DM). Each participant's body mass index (BMI), fasting plasma glucose, fasting insulin concentration, insulin resistance index, and beta-cell function were measured. Sequencing for mtDNA, focusing on exploration of the hypervariable polycytosine tract within the control region, was also conducted in all subjects. RESULTS: Prevalence of the mtDNA 16189 variant was significantly different between DM and non-DM subjects (39.2% vs. 30.7% respectively; P = 0.004). Increased incidence of DM was noted in those harboring the 16189 variant compared with those lacking the variant (multivariate odds ratio, 1.38; 95% confidence interval, 1.07-1.80). Moreover, increased BMI was identified as an aggravating factor for development of DM in subjects harboring the variant. Odds ratio determinations yielded 2.14 in overweight and 4.63 in obese subjects harboring the variant in comparison with subjects without (1.83 in overweight and 2.16 in obese subjects). This is consistent with a progressively increased prevalence of the mtDNA 16189 variant in the non-DM groups with higher fasting insulin concentration, insulin resistance index, and beta-cell function (all P(trend) < 0.005). CONCLUSION: The mtDNA 16189 variant can influence development of T2DM. The demonstrated dynamic between the 16189 variant and increased BMI exemplify an additive effect of genetic and environmental factors on the pathogenesis of T2DM.

Adult↗

PubMed2005

Mitochondrial DNA variants in a portuguese population of patients with Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in late adulthood. Mitochondrial respiratory chain impairment has been detected in the brain, muscle, fibroblasts and platelets of AD patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the etiology of the disease. Several reports have identified mtDNA mutations in AD patients, but there is no consensual opinion regarding the cause of the impairment. We have studied mtDNA NADH dehydrogenase subunit 1 nucleotides 3337-3340, searching for mutations. Our study group included 129 AD patients and 125 healthy age-matched controls. We have found alterations in two AD patients: one had two already known mtDNA modifications (3197 T-C and 3338 T-C) and the other a novel transition (3199 T-C) which, to our knowledge, has not been described before.

Adult↗