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PubMed2000

Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome.

Mitochondrial DNA (mtDNA) variants have been implicated in the pathogenesis of diabetes. A mutation in the tRNA leucine gene at position 3243 has been previously reported in mtDNA of maternally inherited diabetes and deafness (MIDD) patients. Because the true prevalence of the mitochondrial origin in diabetes may be underestimated, we searched for potentially diabetogenic anomalies of mtDNA in 9 patients highly suspected of mitochondrial diabetes selected on maternally inheritance and clinical features. In order to detect high levels of mutant DNA, the mtDNA of muscle sample of 2 patients was totally sequenced and the 22 tRNA genes and flanking sequences of 7 patients were analyzed. A new homoplasmic mutation at position 8381 was found in the ATPase 8 gene of mtDNA of a MIDD patient. The prevalence of three homoplasmic variations (G1888A, T4216G, A4917G) was significantly higher in the small group of MIDD patients compared to controls and other subjects groups. This study demonstrated in our patients sample the high frequency of homoplasmic variations, which could play a role by themselves or in combination, in the pathogenesis of diabetes.

Adult↗
PubMed2003

Increased variation in mtDNA in patients with familial sensorineural hearing impairment.

Analyses of mitochondrial DNA (mtDNA) sequences have revealed non-neutral patterns, suggesting that many amino acid mutations in animal mtDNA may be mildly deleterious, but this has not been verified in human clinical series. Since sensorineural hearing impairment (SNHI) is a common manifestation in many of the syndromes caused by mutations in mtDNA, this may be regarded as the phenotype of choice in attempts to detect mutations that may have a mildly deleterious effect on mitochondrial function. We selected 32 subjects from among 117 unrelated SNHI patients with SNHI in maternal relatives by means of family history, determined the entire coding region sequence of mtDNA and compared the sequence variation with that in 32 haplogroup-matched controls taken at random from 192 Finnish sequences. The 32 control sequences differed from the remaining 160 sequences by 36+/-9 substitutions (mean +/- SD), while the difference for the 32 patients was 58+/-4 substitutions ( P=0.005 for difference; Wilcoxon signed rank test). Differences were also found in the number of new haplotypes and new non-synonymous mutations or mutations in tRNA or rRNA genes. A total of 12 rare mtDNA variants were detected in the patients, and only 3 of these were considered to be neutral in effect. It is proposed that increased sequence variation in mtDNA may be a genetic risk factor for SNHI, and the increased frequency of rare haplotypes in these patients points to the presence of mildly deleterious mutations in mtDNA.

Adenine↗
PubMedDate not supplied

[Diversity of mitochondrial DNA haplotypes in ethnic populations of the Volga-Ural region of Russia].

The mtDNA polymorphism was analyzed in eight ethnic groups (N = 979) of the Volga-Ural region. Most mtDNA variants belonged to haplogroups H, U, T, J, W, I, R, and N1 characteristic of West Eurasian populations. The most frequent were haplogroups H (12-42%) and U (18-44%). East Eurasian mtDNA types (A, B, Y, F, M, N9) were also observed. Genetic diversity was higher in Turkic than in Finno-Ugric populations. The frequency of mtDNA types characteristic of Siberian and Central Asian populations substantially increased in the ethnic groups living closer to the Urals, a boundary between Europe and Asia. Geographic distances, rather than linguistic barriers, were assumed to play the major role in distribution of mtDNA types in the Volga-Ural region. Thus, as concerns the maternal lineage, the Finno-Ugric populations of the region proved to be more similar to their Turkic neighbors rather than to linguistically related Balto-Finnish ethnic groups.

Adult↗
PubMed2000

Inherited variability of the mitochondrial genome and successful aging in humans.

Increasing data indicate that polymorphic variants of nuclear loci can affect rate and quality of aging in humans. However, the mitochondrial genome is another good candidate, because of the central role played by mitochondrial genes in oxidative phosphorylation (OXPHOS) and cell metabolism. A characteristic of the mitochondrial genome (mtDNA) is the high level of interindividual variability that ensues from high mutation rate and unilinear inheritance. Related groups of germline/inherited mtDNA polymorphisms (haplogroups) have been identified as continent-specific sets of stable/ancient/associated restriction fragment length polymorphisms in the mtDNA coding region, representing markers capable of exactly depicting the mtDNA pool of a specific population. The hypothesis can be put forward that mtDNA variants included in a haplogroup may have similar OXPHOS efficiency and therefore act as genetic factors predisposing to individual successful or unsuccessful aging. This idea can be explored by sampling groups of individuals of different ages from a well-defined population and comparing the pools of mtDNA haplogroups between samples. The results obtained by screening mtDNA haplogroups in about 800 Italians of different ages, including more than 200 centenarians, agree with the hypothesis that the inherited variability of the mitochondrial genome is associated with the chance of successful aging and longevity in humans.

Aging↗
PubMed2026

URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.

The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutations. Over the past decade or so, the study of rare somatic mitochondrial DNA (mtDNA) variants has expanded and continues to garner increasing interest in a wide range of research fields. Here, we describe Ultra-Rare Mutation Detection-Sequencing (URMD-Seq), a high-throughput method that combines unique molecular identifier (UMI)-based library preparation and Next Generation Sequencing (NGS) for the accurate and scalable detection of ultra-rare mutations in the mtDNA control region. Our method exploits degenerate primers to label individual mtDNA molecules. This is followed by several purification, quantification and amplification steps, to obtain high quality amplicons for sequencing on the Illumina MiSeq platform. Our approach enables the use of total genomic DNA extract as starting point for the assay, overcoming the need for organelle isolation and/or mtDNA enrichment, hence broadening the type of specimen that can be studied, while offering cost and time benefits. The assay described herein has been demonstrated to reliably measure variants present at on average 0.09%, but as low as 0.03%, variant allele frequency in a variety of tissues, including fresh and frozen biobanked specimens. Using this protocol, library preparation of 300 specimens can be completed by a single individual with general nucleic acid handling experience in approximately 20 days. Given its flexibility and scalability, URMD-Seq is particularly well suited for epidemiological studies using a large number of specimens.

Humans↗
PubMed1991

Polymorphisms in tandemly repeated sequences of Saccharomyces cerevisiae mitochondrial DNA.

A spontaneously arising mitochondrial DNA (mtDNA) variant of Saccharomyces cerevisiae has been formed by two extra copies of a 14-bp sequence (TTAATTAAATTATC) being added to a tandem repeat of this unit. Similar polymorphisms in tandemly repeated sequences have been found in a comparison between mtDNAs from our strain and others. In 5850 bp of intergenic mtDNA sequence, polymorphisms in tandemly repeated sequences of three or more base pairs occur approximately every 400-500 bp whereas differences in 1-2 bp occur approximately every 60 bp. Some polymorphisms are associated with optional G + C-rich sequences (GC clusters). Two such optional GC clusters and one A + T repeat polymorphism have been discovered in the tRNA synthesis locus. In addition, the variable presence of large open reading frames are documented and mechanisms for generating intergenic sequence diversity in S. cerevisiae mtDNA are discussed.

Base Composition↗
PubMed2006

Variants in mitochondrial tRNAGlu, tRNAArg, and tRNAThr may influence the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in three Han Chinese families with hearing loss.

We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of hearing loss including severity, age-at-onset, audiometric configuration in these subjects. Penetrances of hearing loss in BJ107, BJ108, and BJ109 pedigrees are 35%, 63%, and 67%, respectively. Mutational analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic A1555G mutation and distinct sets of mitochondrial DNA (mtDNA) variants belonging to haplogroups N, F, and M, respectively. Of these variants, the A14693G mutation in the tRNA(Glu), the T15908C mutation in the tRNA(Thr), and the T10454C mutation in the tRNA(Arg) are of special interest as these mutations occur at positions which are highly evolutionarily conserved nucleotides of corresponding tRNAs. These homoplasmic mtDNA mutations were absent among 156 unrelated Chinese controls. The A14693G and T10454C mutations occur at the highly conserved bases of the TpsiC-loop of tRNA(Glu) and tRNA(Arg), respectively. Furthermore, the T15908C mutation in the tRNA(Thr) disrupts a highly conserved A-U base-pairing at the D-stem of this tRNA. The alteration of structure of these tRNAs by these mtDNA mutations may lead to a failure in tRNA metabolism, thereby causing impairment of mitochondrial translation. Thus, mitochondrial dysfunctions, caused by the A1555G mutation, would be worsened by these mtDNA mutations. Therefore, these mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees.

Base Pairing↗
PubMed2005

Only male matrilineal relatives with Leber's hereditary optic neuropathy in a large Chinese family carrying the mitochondrial DNA G11778A mutation.

We report here the characterization of a five-generation large Chinese family with Leber's hereditary optic neuropathy (LHON). Very strikingly, six affected individuals of 38 matrilineal relatives (17 females/21 males) are exclusively males in this Chinese family. These matrilineal relatives in this family exhibited late-onset/progressive visual impairment with a wide range of severity, ranging from blindness to normal vision. The age of onset in visual impairment varies from 17 to 30 years. Sequence analysis of the complete mitochondrial genome in this pedigree revealed the presence of the G11778A mutation in ND4 gene and 29 other variants. This mitochondrial genome belongs to the Southern Chinese haplogroup B5b. We showed that the G11778A mutation is present at near homoplasmy in matrilineal relatives of this Chinese family but not in 164 Chinese controls. Incomplete penetrance of LHON in this family indicates the involvement of modulatory factors in the phenotypic expression of visual dysfunction associated with the G11778A mutation. However, none of other mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and phenotypic variability of LHON in this Chinese family carrying the G11778A mutation.

Asian People↗
PubMed2001

Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families.

Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression.

Adolescent↗
PubMed2026

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Humans↗
PubMedDate not supplied

[Phylogeografic analysis of mitochondrial DNA Nogays: the high level of mixture of maternal lineages from Eastern and Western Eurasia].

Analysis of markers mtDNA in a population of Nogays (n = 206), living on Nothern Caucasus and speaking on language of Turkic branch of the Altaic linguistic family, has shown, that the level of their genetic differentiation is high (H = 0.99). Among the found haplotypes there is all the basic Western Eurasian haplogroups, most often of which are clusters H (22%) and U (21%), however, the percentage of the lineages specific only for populations of East Eurasia (40%) is highest. In a population of Nogays there are also variants mtDNA, belonging to haplogroup M1, characteristic for North East Africa, and gaplogroup U2, typical for populations of India. This testifies about presence in a gene pool of Nogays people of components of a various parentage.

Asia↗
PubMed1996

Characterization of the mitochondrial DNA in patients with multiple sclerosis.

Mitochondrial DNA (mtDNA) abnormalities with primary pathogenic significance for optic nerve atrophy have been detected in inflammatory demyelinating conditions indistinguishable from multiple sclerosis (MS). However, the degree of involvement of mtDNA alterations in the pathogenesis of MS is not clear. To further clarify this question, we sequenced the entire mtDNA in three MS patients. A number of nucleotide alterations were defined relative to the standard mtDNA sequence in each patient. After excluding the silent mutations and common polymorphisms, eight unusual mtDNA variants within the ribosomal (r) RNA, transfer (t) RNA or protein encoding regions were identified and characterized. Two mutations remained as putative MS related alterations after screening a population of 49 patients and 63 controls for the presence of these mutations. An A to G transition at nucleotide (nt) 13966 causing a threonine to phenylalanine exchange in a non-conserved region of the ND-5 was detected in two independent MS patients and in none of the sixty-three controls or in any of the large control population in the literature. The second mutation of interest at 14798 is a T to C transition changing a phenylalanine to leucine in a relatively conserved domain of the cytochrome b. Although it is a known polymorphism, a tendency for prominent optic nerve involvement was observed among patients carrying this mutation. As we have performed the first complete mtDNA sequence analysis on MS patients, we conclude that MS may occur without mtDNA abnormalities of primary pathogenic significance. However, contribution of the mtDNA to genetic susceptibility or phenotypic presentation of MS is possible in certain subgroups of patients, and merits further investigation.

Adult↗
PubMed1998

European Y-chromosomal lineages in Polynesians: a contrast to the population structure revealed by mtDNA.

We have used Y-chromosomal polymorphisms to trace paternal lineages in Polynesians by use of samples previously typed for mtDNA variants. A genealogical approach utilizing hierarchical analysis of eight rare-event biallelic polymorphisms, seven microsatellite loci, and internal structural analysis of the hypervariable minisatellite, MSY1, has been used to define three major paternal-lineage clusters in Polynesians. Two of these clusters, both defined by novel MSY1 modular structures and representing 55% of the Polynesians studied, are also found in coastal Papua New Guinea. Reduced Polynesian diversity, relative to that in Melanesians, is illustrated by the presence of several examples of identical MSY1 codes and microsatellite haplotypes within these lineage clusters in Polynesians. The complete lack of Y chromosomes having the M4 base substitution in Polynesians, despite their prevalence (64%) in Melanesians, may also be a result of the multiple bottleneck events during the colonization of this region of the world. The origin of the M4 mutation has been dated by use of two independent methods based on microsatellite-haplotype and minisatellite-code diversity. Because of the wide confidence limits on the mutation rates of these loci, the M4 mutation cannot be conclusively dated relative to the colonization of Polynesia, 3,000 years ago. The other major lineage cluster found in Polynesians, defined by a base substitution at the 92R7 locus, represents 27% of the Polynesians studied and, most probably, originates in Europe. This is the first Y-chromosomal evidence of major European admixture with indigenous Polynesian populations and contrasts sharply with the picture given by mtDNA evidence.

Alleles↗
PubMed1999

Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. Mutation in brief no. 237. Online.

We have characterised three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. The first of these was a G to A substitution in the 5' splice junction of exon 4 which generated an mRNA that lacked exon 4. The second was a nonsense mutation in exon 5 which changed the arginine residue at position 142 to a stop codon, and the third mutation, also in exon 5, was a triple base substitution from nucleotide position 417 to 419. This mutation encompassed two codons but only changed the amino acid predicted from the second codon, resulting in the replacement of valine with glutamine at position 134. This missense mutation has been described previously by Meguro et al. 1994, on one allele in a compound heterozygote with hepatoerythropoietic porphyria. This is the third case of an hepatoerythropoietic porphyria mutation in an individual diagnosed with familial porphyria cutanea tarda.

Humans↗
PubMed2001

Brief communication: paleoanthropology and the population genetics of ancient genes.

The Mezmaiskaya cave mtDNA is similar in many ways to the Feldhofer cave Neandertal sequence and the more recently obtained Vindija cave sequence. If we accept the contention that the Mezmaiskaya cave specimen is a Neandertal infant, its mtDNA provides no new information about the fate of the European Neandertals. However, there is reason to believe that the Mezmaiskaya cave infant is not a Neandertal, and this places its importance in another light, because it delimits the possible hypotheses of Neandertal and recent human genetic relationships. One possibility is a that the pattern found in ancient mtDNA results from the replacement of an isolated gene pool (Neandertals) by one of its contemporaries (modern humans). A second possibility is natural selection expressed as the substitution of an advantageous mtDNA variant within a single large species, including both Neandertals and modern humans. The geologic, archaeological, and dating evidence shows the Mezmaiskaya cave infant to be a burial from a level even more recent than the Upper Paleolithic preserved at the site, and its anatomy does not contradict the assessment that the Mezmaiskaya cave infant is not a Neandertal. Therefore, the second pattern can be favored over the first.

Animals↗
PubMed1997

Transmission of mitochondrial DNA--playing favorites?

Mitochondria are essential subcellular organelles containing an extranuclear genome (mtDNA). Mutations in mtDNA have recently been identified as causing a variety of human hereditary disease. In most of these cases, the tissues of the affected individual contain a mixture of mutant and normal mtDNA, with this ratio determining the severity of symptoms. Stochastic factors alone have generally been believed to determine this ratio. Jenuth et al.(1), however, examining mice that contain a mixture of mtDNA types, show evidence of strong selective forces at work in favoring one mtDNA variant over another in some tissues.

Animals↗
PubMed2006

Heteroplasmy as a common state of mitochondrial genetic information in plants and animals.

Plant and animal mitochondrial genomes, although quite distinct in size, structure, expression and evolutionary dynamics both may exhibit the state of heteroplasmy--the presence of more than one type of mitochondrial genome in an organism. This review is focused on heteroplasmy in plants, but we also highlight the most striking similarities and differences between plant and animal heteroplasmy. First we summarize the information on heteroplasmy generation and methods of its detection. Then we describe examples of quantitative changes in heteroplasmic populations of mitochondrial DNA (mtDNA) and consequences of such events. We also summarize the current knowledge about transmission and somatic segregation of heteroplasmy in plants and animals. Finally, factors which influence the stoichiometry of heteroplasmic mtDNA variants are discussed. Despite the apparent differences between the plant and animal heteroplasmy, the observed similarities allow one to conclude that this condition must play an important role in the mitochondrial biology of living organisms.

Animals↗
PubMed2003

PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma.

Thyroid oncocytomas are tumors characterized by dense mitochondrial accumulation, the cause of which is currently unknown. Members of the PGC-1 coactivator family have been identified as important mediators of mitochondrial biogenesis because of their ability to activate nuclear genes encoding mitochondrial proteins. We have investigated the influence of the PGC-1 related coactivator (PRC) on the high mitochondrial content observed in oncocytoma by quantifying the transcripts of PRC, the nuclear respiratory factor 1 (NRF-1) and the mitochondrial transcription factor A (TFAM), in 30 oncocytic tumors and corresponding normal tissues. The three genes studied were found to be significantly overexpressed in thyroid oncocytomas, concomitantly with an increase in cytochrome oxidase activity and mitochondrial DNA (mtDNA) content. However, no mtDNA variant in the D-loop region appeared to be involved in oncocytic development. We conclude that overexpression of the PRC pathway is responsible for mitochondrial proliferation in the context of thyroid oncocytoma.

Adenoma↗