SEARCH · PubMed Health

Results for “mtDNA variants”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources

PubMed2006

De novo COX2 mutation in a LHON family of Caucasian origin: implication for the role of mtDNA polymorphism in human pathology.

Recent studies suggest that certain mutations with phylogeographic importance as haplogroup markers may also influence the phenotypic expression of particular mitochondrial disorders. One such disorder, Leber's hereditary optic neuropathy (LHON), demonstrates a clear expression bias in mtDNAs belonging to haplogroup J, a West Eurasian maternal lineage defined by polymorphic markers that have been called 'secondary' disease mutations. In this report, we present evidence for a de novo heteroplasmic COX2 mutation associated with a LHON clinical phenotype. This particular mutation-at nucleotide position 7,598-occurs in West Eurasian haplogroup H, the most common maternal lineage among individuals of European descent, whereas previous studies have detected this mutation only in East Eurasian haplogroup E. A review of the available mtDNA sequence data indicates that the COX2 7598 mutation occurs as a homoplasic event at the tips of these phylogenetic branches, suggesting that it could be a variant that is rapidly eliminated by selection. This finding points to the potential background influence of polymorphisms on the expression of mild deleterious mutations such as LHON mtDNA defects and further highlights the difficulties in distinguishing deleterious mtDNA changes from neutral polymorphisms and their significance in the development of mitochondriopathies.

Adult↗

PubMed1997

Discordant phylogeographic patterns between the Y chromosome and mitochondrial DNA in the house mouse: selection on the Y chromosome?

We have compared patterns of geographic variation and molecular divergence of mitochondrial DNA (mtDNA) and Y chromosome over the range of the different subspecies of Mus musculus. MtDNA was typed for 305 nucleotides in the control region, the Y chromosome for 834 base pairs (bp) in Zfy introns and 242 bp in Sry, a Zfy2 18-bp deletion, and two microsatellites. Apparent discrepancies exist between the distributions of the lineages of mtDNA and of the two major Y-chromosome lineages thus defined: some subspecies share the same mtDNA lineage but have different Y-chromosome lineages or vice versa. One microsatellite reveals a geographically clustered variation inside the distribution of each Y-chromosome lineage, showing that new Y-chromosome variants can rapidly spread locally. The two major Y-chromosome lineages have a divergence time only about one fourth of that between mtDNA lineages. Although this recent coalescence of the Y chromosomes between subspecies could partly be due to a lower ancestral polymorphism of the Y chromosome, it suggests that secondary introgression after the radiation of the subspecies might have occurred. There is evidence that the differentiation of the Y-chromosome lineages contributes to partial reproductive isolation between subspecies, and patterns of molecular evolution suggest that selection has played a role in the rapid spread across subspecies.

Animals↗

PubMed2006

Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations.

Knowledge about the world phylogeny of human mitochondrial DNA (mtDNA) is essential not only for evaluating the pathogenic role of specific mtDNA mutations but also for performing reliable association studies between mtDNA haplogroups and complex disorders. In the past few years, the main features of the East Asian portion of the mtDNA phylogeny have been determined on the basis of complete sequencing efforts, but representatives of several basal lineages were still lacking. Moreover, some recently published complete mtDNA sequences did apparently not fit into the known phylogenetic tree and conflicted with the established nomenclature. To refine the East Asian mtDNA tree and resolve data conflicts, we first completely sequenced 20 carefully selected mtDNAs--likely representatives of novel sub-haplogroups--and then, in order to distinguish diagnostic mutations of novel haplogroups from private variants, we applied a 'motif-search' procedure to a large sample collection. The novel information was incorporated into an updated East Asian mtDNA tree encompassing more than 1000 (near-) complete mtDNA sequences. A reassessment of the mtDNA data from a series of disease studies testified to the usefulness of such a refined mtDNA tree in evaluating the pathogenicity of mtDNA mutations. In particular, the claimed pathogenic role of mutations G3316A, T3394C, A4833G and G15497A appears to be most questionable as those initial claims were derived from anecdotal findings rather than e.g. appropriate association studies. Following a guideline based on the phylogenetic knowledge as proposed here could help avoiding similar problems in the future.

Asian People↗

PubMed2002

Traces of early Eurasians in the Mansi of northwest Siberia revealed by mitochondrial DNA analysis.

The mitochondrial DNA (mtDNA) of 98 Mansi, an ancient group (formerly known as "Vogul") of Uralic-speaking fishers and hunters on the eastern slope of the northern Ural Mountains, were analyzed for sequence variants by restriction fragment--length polymorphism analysis, control-region sequencing, and sequencing of additional informative sites in the coding region. Although 63.3% of the mtDNA detected in the Mansi falls into western Eurasian lineages (e.g., haplogroups UK, TJ, and HV), the remaining 36.7% encompass a subset of eastern Eurasian lineages (e.g., haplogroups A, C, D, F, G, and M). Among the western Eurasian lineages, subhaplogroup U4 was found at a remarkable frequency of 16.3%, along with lineages U5, U7, and J2. This suggests that the aboriginal populations residing immediately to the east of the Ural Mountains may encompass remnants of the early Upper Paleolithic expansion from the Middle East/southeastern Europe. The added presence of eastern Eurasian mtDNA lineages in the Mansi introduces the possibilities that proto-Eurasians encompassed a range of macrohaplogroup M and N lineages that subsequently became geographically distributed and that the Paleolithic expansion may have reached this part of Siberia before it split into western and eastern human groups.

Asia↗

PubMed2005

Characterization and prevalence of a circular mitochondrial plasmid in senescence-prone isolates of Neurospora intermedia.

Genetic and molecular analyses of the phenomenon of senescence-i.e., irreversible loss of growth and reproductive potential upon subculturing-in Neurospora intermedia strain M1991-60A, collected from Maddur in southern India, showed the presence of plasmid pMaddur1, which is homologous to the senescence-inducing circular mitochondrial plasmid, pVarkud. Maternal inheritance of senescence in M1991-60A correlated to the formation of variant pMaddur1, its subsequent insertion into mitochondrial (mt)DNA and the accumulation of defective mtDNA with the pMaddur1insert. PCR-based analyses for similar plasmids in 147 natural isolates of Neurospora from Maddur showed that nearly 40% of the strains had pMaddur1 or pMaddur2 that shared 97-98% sequence homology with pVarkud and pMauriceville. Nearly 50% of the strains that harbored either pMaddur1 or pMaddur2, also contained a circular Varkud satellite plasmid (pVS). Size polymorphism maps to the cluster of PstI sites in the non-coding region. Whereas senescence of nearly 40% of N. intermedia strains may be due to pMaddur, the presence in seven strains of pVS but not pMaddur and the absence of either of these two plasmids in other senescence-prone isolates suggests yet undiscovered mechanisms of senescence in the Maddur strains.

Cellular Senescence↗

PubMed2000

[Variability of nucleotide sequences of the mitochondrial DNA cytochrome c gene in dolly varden and taranetz char].

Nucleotide sequence of the 307-bp fragment of the mitochondrial DNA cytochrome b gene was determined in representatives of the three species of the Salvelinus genus, specifically, dolly varden char (S. malma), taranetz char (S. taranetzi), and white-spotted char (S. leucomaenis). These results pointed to a high level of mitochondrial DNA (mtDNA) divergence between white-spotted char and dolly varden char, on the one hand, and taranetz char, on the other (the mean d value was 5.45%). However, the divergence between the dolly varden char and taranetz char was only 0.81%, which is comparable with the level of intraspecific divergence in the dolly varden char (d = 0.87%). It was shown that the dolly varden char mitochondrial gene pool contained DNA lineages differing from the main mtDNA pool at least in the taranetz char-specific mitochondrial lineages. One of these dolly varden char mtDNA lineages was characterized by the presence of the restriction endonuclease MspI-D variant of the cytochrome b gene. This lineage was widely distributed in the Chukotka populations but it was not detected in the Yana River (Okhotsk sea) populations. These findings suggest that dolly varden char has a more ancient evolutionary lineage, diverging from the common ancestor earlier than did taranetz char.

Animals↗

PubMed2001

Maternally inherited deafness associated with a T1095C mutation in the mDNA.

Hearing loss is a relatively frequent defect in children with a genetic or predisposition basis in about 50% of cases. Mitochondrial DNA (mtDNA)-associated disorder often present with sensorineural hearing loss (SNHL) either in isolation or as a part of a multisystem disorder in adults but the frequency in pediatric cases is unknown. We analysed deafness-related mtDNA mutations in 80 deaf children to assess the relative frequency of alterations in childhood-onset SNHL. In 16 patients in whom maternal inheritance was possible, we screened for new mutations likely to affect mitochondrial protein synthesis. In one child we detected a novel mutation (T1095C) in the 12S rRNA gene. This mutation fulfils the suggested criteria for definition of a disease-related nucleotide variant. No mutations were found in other patients. Although we cannot exclude the presence of still undefined new mtDNA mutations, our data suggest that mtDNA defect are not common in childhood-onset SNHL.

Base Sequence↗

PubMed1999

Cytonuclear disequilibria in wild populations of rabbit (Oryctolagus cuniculus L.) suggest unequal allele turnover rates at the b locus (IGKC1).

DNA sequence comparisons suggest that evolutionary rates at the rabbit IGKC1 locus can differ among allelic lineages. Here we address the question of whether population turnover rates can vary among IGKC1 alleles. We studied the distribution of sixteen IGKC1 (or b-locus) allotypes in areas comprising the aboriginal species range (Iberian peninsula). Rabbits in this area belong to one of two distantly related mitochondrial lineages (mtDNA types) A and B. In the more recent distribution area of the species, all rabbits belong to the mtDNA type B lineage, and IGKC1 alleles b4 and b5 comprise over 90% of the gene pool. These two alleles are also predominant in areas of mtDNA type B prevalence within the Iberian range. However, in areas of mtDNA type A prevalence, the b4 and b5 allotypes are rare or absent; they apparently have been replaced by serologically related, but distinct, 'endemic' variants. The cytonuclear disequilibria were highly significant, also within the subsample consisting of populations from Spain. These observations suggest that allelic persistence times for the predominant IGKC1 lineages could be shorter than the divergence time of the major mtDNA lineages A and B. In contrast, the relative gene frequencies of the IGKC1 allele b9 were similar among the type A and type B rabbits; it was present in most populations at low frequency. In consequence, persistence times of the b9 allele appear to be longer than the divergence time of lineages A and B. The data reported here are in agreement with the DNA sequence data, providing further proof that the molecular clock can run at different rates among allelic lineages at the rabbit IGKC1 locus.

Alleles↗

PubMed2006

Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter.

Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-gamma (PPAR-gamma) coactivator-1 alpha (PGC-1alpha) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1alpha coding region and insulin resistance has been reported in some ethnic groups. In this study, we investigated whether a change of glycine to serine at codon 482 of PGC-1alpha affected the Tfam promoter activity. The cDNA of PGC-1alpha variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1alpha protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1alpha genotype G1444A and mitochondrial DNA (mtDNA) copy number from 229 Korean leukocyte genomic DNAs. Subjects with Gly/Gly had a 20% lower amount of peripheral blood mtDNA than did subjects with Gly/Ser and Ser/Ser (p<0.05). No correlation was observed between diabetic parameters and PGC-1alpha genotypes in Koreans. These results suggest that PGC-1alpha variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication.

Amino Acid Substitution↗

PubMed1997

[The origin of caucasoid BamHI-3/MspI-4 mitochondrial DNA marker].

According to the analysis of polymorphism of mitochondrial DNA (mtDNA) in eastern Slavs, the frequency of the BamHI-3/AvaII-9/MspI-4 and BamHI-3/AvaII-13/MspI-4 mitotypes are 14% and 3%, respectively. The mitotype BamHI-3/MspI-4 in relation to the (+)AluI/15606 variant was demonstrated to be identical in European populations. It is assumed that the unimodal distribution of the difference values between all pairs of nucleotide sequences of the control mtDNA region that correspond to the BamHI-3/MspI-4 mitogroup indicates an association between the increase of mitotypic diversity in this mitogroup and the exponential growth of European populations in the Neolithic period.

DNA, Mitochondrial↗

PubMed2004

Effects of purifying and adaptive selection on regional variation in human mtDNA.

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

Adaptation, Physiological↗

PubMed2003

Detection of mitochondrial DNA mutations in gestational trophoblastic disease.

Mitochondrial DNA (mtDNA) mutations have been implicated in a wide range of human disease. However, its role in gestational trophoblastic disease remains unclear. In this study, the entire mitochondrial genome of 10 hydatidiform moles (HM) and one choriocarcinoma were examined by automated DNA sequencing after amplification by polymerase chain reaction. MtDNA sequences obtained separately from disease tissues (HM and choriocarcinoma) and patients' tissues were compared. Of the 133 neutral sequence variants identified, 41 have not been reported to date. Large or small-scale deletion or insertion was not detected in any of the samples studied. A total of six (five in the D-loop and one in the 16S rRNA gene) somatic point mutations were detected in the choriocarcinoma sample, in contrast to none being detected in the HM samples. Somatic mtDNA instability was detected in the D-loop region in three cases of HM as well as in the choriocarcinoma sample. Somatic mtDNA instability appeared in the same nucleotide position, from 303 to 309, within the Conserved Sequence Block II resulting in alteration in length of the homopolymorphic C-tract, reflecting microsatellite instability. The results suggest that mtDNA instability may be an early event occurring at a premalignant stage. Occurrence of multiple somatic mtDNA mutations in choriocarcinoma suggests that mtDNA mutations might play an important role in the molecular pathogenesis of invasive gestational trophoblastic disease.

Choriocarcinoma↗

PubMed2004

Mitochondrial-DNA nucleotides G4298A and T10010C as pathogenic mutations: the confirmation in two new cases.

Mitochondrial encephalomyopathies are highly variable clinically and at the genetic level. In practice, when the mitochondrial DNA (mtDNA) of any mitochondrial-patient is sequenced, a very high number of variations are noted. The vast majority of these differences are simply polymorphisms, that is, non-pathologic, homoplasmic sequence variations; however, when a heteroplasmic variant is detected (co-existence of two different populations in the same tissue) this is clinically significant. We identified two different heteroplasmic mutations in the mtDNA of two subjects: G4298A in the tRNA(Ala) (Alanine) gene and T10010C in the tRNA(Gly) (Glycine), both of which have been reported previously. This work confirms the pathogenicity of these mutations and helps define the correlation between genotype and phenotype.

Journal Article↗

PubMed2005

Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal).

We analyzed the control region of the mitochondrial DNA (mtDNA) from maternally related individuals originating from the Azores Islands (Portugal) in order to estimate the mutation rate of mtDNA and to gain insights into the process by which a new mutation arises and segregates into heteroplasmy. Length and/or point heteroplasmies were found at least in one individual of 72% of the studied families. Eleven new point substitutions were found, all of them in heteroplasmy, from which five appear to be somatic mutations and six can be considered germinal, evidencing the high frequency of somatic mutations in mtDNA in healthy young individuals. Different values of the mutation rate according to different assumptions were estimated. When considering all the germinal mutations, the value of the mutation rate obtained is one of the highest reported so far in family studies. However, when corrected for gender (assuming that the mutations present in men have the same evolutionary weight of somatic mutations because they will inevitably be lost) and for the probability of intraindividual fixation, the value for the mutation rate obtained for HVRI and HVRII (0.2415 mutations/site/Myr) was in the upper end of the values provided by phylogenetic estimations. These results indicate that the discrepancy, that has been reported previously, between the human mtDNA mutation rates observed along evolutionary timescales and the estimations obtained using family pedigrees can be minimized when corrections for gender proportions in newborn individuals and for the probability of intraindividual fixation are introduced. The analyses performed support the hypothesis that (1) in a constant, tight bottleneck genetic drift alone can explain different patterns of heteroplasmy segregation and (2) in neutral conditions, the destiny of a new mutation is strictly related to the initial proportion of the new variant. Another important point arising from the data obtained is that, even in the absence of a paternal contribution of mtDNA, recombination may occur between mtDNA molecules present in an individual, which is only observable if it occurs between mtDNA types that differ at two or more positions.

Azores↗

PubMed2006

Origin and expansion of haplogroup H, the dominant human mitochondrial DNA lineage in West Eurasia: the Near Eastern and Caucasian perspective.

More than a third of the European pool of human mitochondrial DNA (mtDNA) is fragmented into a number of subclades of haplogroup (hg) H, the most frequent hg throughout western Eurasia. Although there has been considerable recent progress in studying mitochondrial genome variation in Europe at the complete sequence resolution, little data of comparable resolution is so far available for regions like the Caucasus and the Near and Middle East-areas where most of European genetic lineages, including hg H, have likely emerged. This gap in our knowledge causes a serious hindrance for progress in understanding the demographic prehistory of Europe and western Eurasia in general. Here we describe the phylogeography of hg H in the populations of the Near East and the Caucasus. We have analyzed 545 samples of hg H at high resolution, including 15 novel complete mtDNA sequences. As in Europe, most of the present-day Near Eastern-Caucasus area variants of hg H started to expand after the last glacial maximum (LGM) and presumably before the Holocene. Yet importantly, several hg H subclades in Near East and Southern Caucasus region coalesce to the pre-LGM period. Furthermore, irrespective of their common origin, significant differences between the distribution of hg H sub-hgs in Europe and in the Near East and South Caucasus imply limited post-LGM maternal gene flow between these regions. In a contrast, the North Caucasus mitochondrial gene pool has received an influx of hg H variants, arriving from the Ponto-Caspian/East European area.

Asia, Western↗

PubMed2005

Lack of mitochondrial DNA divergence between chromosome races of the common shrew, Sorex araneus, in Sweden. Implications for interpreting chromosomal evolution and colonization history.

The common shrew, Sorex araneus, has one of the most variable karyotypes among mammals, displaying numerous chromosome races throughout its distribution. The six chromosome races present in Sweden can be categorized in two different karyotypic groups, the west and north European karyotypic groups (western and northern). Three races belonging to the western group are considered to have arisen through whole arm reciprocal translocations (WARTs). Race formation through this process requires a bottleneck event. In the present study we sequenced a part of the mitochondrial DNA (mtDNA) genome to investigate molecular differences between the chromosome races in Sweden. We found no mtDNA differentiation between the mainland chromosome races or the karyotypic groups. Genetic variation is as large between populations within a race as between populations among the races or karyotypic groups, suggesting that the karyotypic groups might have originated in a common glacial refugium. The noticeable exception is the Oland race, which shows higher mtDNA diversity compared to the other Swedish races, indicating a divergent origin difficult to explain. Mitochondrial DNA variation in Sweden suggests that most haplotypes arose in situ and that the populations has undergone a rapid size expansion. Altogether, the mtDNA data are in agreement with the WART hypothesis, which still holds as the most plausible variant of karyotype evolution for three of the chromosome races of the common shrew in Sweden.

Animals↗

PubMed2002

A case of Kearns-Sayre syndrome with autoimmune thyroiditis and possible Hashimoto encephalopathy.

The Kearns-Sayre syndrome (characterized by onset before 20, chronic ophthalmoplegia, pigmentary retinal degeneration and at least 1 of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia (CPEO) with frequent re-arrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c oxidase in many muscle fibers, autoimmune thyroiditis followed by depressive phobic disturbances, slowing EEG, hyperreflexia, tremor and visual hallucinations, in which the diagnosis of possible encephalopathy associated with autoimmune thyroid disease (Hashimoto encephalopathy) was made. We speculated that in this patient, predisposed by mitochondrial deletion, anti-thyroid antibodies may have interfered with mitochondrial cerebral function, causing Hashimoto encephalopathy and facilitating ophthalmoplegia. It seems important to study anti-thyroid antibodies in every case of Kearns-Sayre syndrome, specially if ophthalmoplegia is recent, even in order to the therapy.

Brain Diseases↗

PubMed2002

Primary and secondary defects of the mitochondrial respiratory chain.

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.

Animals↗