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PubMed2000

Complex mitochondriopathy associated with 4 mtDNA transitions.

In a 33-year-old man, mitochondriopathy was diagnosed upon short stature, auditory impairment, gynaecomastia, hypogonadism, vertical ophthalmoplegia, cerebral atrophy, leucencephalopathy, cataract, hypertrabeculated left ventricle, hypothyroidism, diabetes mellitus, glomerulonephritis necessitating kidney transplantation, general wasting, polyneuropathy, abnormally high lactate levels on exercise, partially reduced cytochrome-c oxidase staining and abnormally structured mitochondria on muscle biopsy. Mitochondrial DNA (mtDNA) analysis revealed 1 novel (A15662G) and 3 known mtDNA transition(s) (T3398C, T4216C, G15812A) affecting the cytb and ND1 gene, respectively. Three of the patient's transitions were also detected in blood leukocytes of the patient's maternal grandmother, mother and brother. Mutant mtDNA was heteroplasmic at >75% in the patient's skeletal muscle.

Adult↗
PubMed1994

The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families.

The point mutation at bp 8993 of human mtDNA in the ATPase 6 gene is associated with neurogenic weakness, ataxia and retinitis pigmentosa, and with subacute necrotizing encephalomyelopathy (Leigh disease) when present at high copy number. In this study we describe three new multiplex families with the ATPase 8993 mtDNA mutation and demonstrate a correlation between the percentage heteroplasmy of this mutation and the clinical phenotype. By combining this study with previous data we produce a graph of age of onset of symptoms versus percentage heteroplasmy of the mutation. Finally, we determine that ATP synthesis with NAD-linked substrates in cultured lymphoblast mitochondria from three patients with Leigh disease who had a high percentage heteroplasmy was on average 66% of the rate seen in control lymphoblast mitochondria. Similar rates are observed in lymphoblast mitochondria isolated from patients with Leigh disease due to complex I deficiency. This percentage appears to be independent of the rate of electron transport in mitochondria from patient cell lines with the mtDNA 8993 mutation.

Adenosine Triphosphatases↗
PubMed2006

Deep mtDNA divergences indicate cryptic species in a fig-pollinating wasp.

BACKGROUND: Figs and fig-pollinating wasps are obligate mutualists that have coevolved for ca. 90 million years. They have radiated together, but do not show strict cospeciation. In particular, it is now clear that many fig species host two wasp species, so there is more wasp speciation than fig speciation. However, little is known about how fig wasps speciate. RESULTS: We studied variation in 71 fig-pollinating wasps from across the large geographic range of Ficus rubiginosa in Australia. All wasps sampled belong to one morphological species (Pleistodontes imperialis), but we found four deep mtDNA clades that differed from each other by 9-17% nucleotides. As these genetic distances exceed those normally found within species and overlap those (10-26%) found between morphologically distinct Pleistodontes species, they strongly suggest cryptic fig wasp species. mtDNA clade diversity declines from all four present in Northern Queensland to just one in Sydney, near the southern range limit. However, at most sites multiple clades coexist and can be found in the same tree or even the same fig fruit and there is no evidence for parallel sub-division of the host fig species. Both mtDNA data and sequences from two nuclear genes support the monophyly of the "P. imperialis complex" relative to other Pleistodontes species, suggesting that fig wasp divergence has occurred without any host plant shift. Wasps in clade 3 were infected by a single strain (W1) of Wolbachia bacteria, while those in other clades carried a double infection (W2+W3) of two other strains. CONCLUSION: Our study indicates that cryptic fig-pollinating wasp species have developed on a single host plant species, without the involvement of host plant shifts, or parallel host plant divergence. Despite extensive evidence for coevolution between figs and fig wasps, wasp speciation may not always be linked strongly with fig speciation.

Animals↗
PubMed2005

Possibility of selection against mtDNA mutations in tumors.

Several studies of tumors have revealed substantial numbers of clonally expanded somatic mutations in mitochondrial DNA (mtDNA), not observed in adjacent intact tissues. These findings were interpreted as indicating the involvement of mtDNA mutations in tumorigenesis. Such comparisons, however, ignore an important confounding factor: the monoclonal origin of tumors as opposed to the highly polyclonal nature of normal tissues. Analysis of recently published data on the incidence of somatic mutations in nontumor monoclonal cells suggests that, contrary to the prevailing view, the process of tumorigenesis may be accompanied by active selection against detrimental mtDNA mutations.

DNA, Mitochondrial↗
PubMed2004

Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production.

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 microM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45-) cell proliferation was 2.5 microM (SD+/-0.7) and 0.023 microM (SD+/-0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD+/-23) at 10 microM AZT and in erythroid-rich cultures it increased by 134% (SD+/-24) in the presence of 0.5 microM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 microM, whereas in erythroid rich cultures this AZT IC50 was < 0.0005 microM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

Anti-HIV Agents↗
PubMed2005

Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.

The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.

Adult↗
PubMed1995

Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation.

In vivo phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective brain and muscle energy metabolism in three affected siblings in a family with Leber's hereditary optic neuropathy (LHON) with the 11778 mtDNA mutation. We studied 14 nonaffected members of the same pedigree by 31P-MRS and molecular genetics. Nine of 14 individuals studied had the 11778 mtDNA mutation, with various degrees of heteroplasmy. A decreased brain energy reserve, as shown by low phosphocreatine content and phosphorylation potential and high [ADP], was present in eight of these nine subjects with the 11778 mutation. A low rate of postexercise phosphocreatine recovery in muscle was present in six of the nine mutated individuals. Normal MRS findings in the brain of one and the muscle of three carriers were accompanied by a low percentage of mutated mtDNA. All subjects without mutation had normal brain and muscle MRS. 31P-MRS disclosed defective bioenergetics in the brain or muscle or both of all asymptomatic carriers studied from our pedigree.

Adenosine Diphosphate↗
PubMed1997

Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation.

To obtain a better molecular definition of patients with syndromic retinitis pigmentosa, we screened for mitochondrial DNA (mtDNA) alterations of the two ATPase genes and 22 tRNA-coding sequences in 10 patients whose features resembled NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. In two patients, one of whom showed features mimicking Kearns-Sayre syndrome, we identified a heteroplasmic T8993G mutation (average 80%) in the mitochondrial ATPase 6 gene. There was no mutated mtDNA in muscle and leukocytes from the mother of one patient or in leukocytes from his brother, suggesting a rapid segregation of the mutated nucleotide. MtDNA analysis should be considered in the differential diagnosis of patients with syndromic retinitis pigmentosa.

Adult↗
PubMed2003

Hypersensitive PCR, ancient human mtDNA, and contamination.

When highly efficient polymerase was used with high cycle numbers (50-60), strong amplifications were observed, but negative controls were also unexpectedly amplified in a study of ancient human mtDNA from 2000-year-old skeletons. The results of a series of tests revealed that the hypersensitive polymerase chain reaction (PCR) generated by higher cycles and the presence of contaminant DNA (though at extremely low levels) should be responsible for the amplification of negative controls. We suggest that PCR sensitivity be optimized to take advantage of highly efficient polymerase and at the same time prevent "background DNA" from becoming "contaminant DNA" and obscuring the analysis of authentic ancient DNA. We propose the use of multiple positive controls when amplifying ancient human mtDNA samples to indicate the sensitivity of individual PCR amplifications and to monitor the contamination levels of modern human DNA. This study provides some suggestions as to how to amplify and analyze ancient human mtDNA when unavoidable and extremely tiny amounts of modern human DNA exist.

Archaeology↗
PubMed2005

African female heritage in Iberia: a reassessment of mtDNA lineage distribution in present times.

The Iberian peninsula is a peripheral region of Europe in close proximity to Africa. Its inhabitants have an overall mtDNA genetic landscape typical of European background, although with signs of some African influence, whose features we deemed to disclose by analyzing available mtDNA HVRI distributions and new data. We analyzed 1,045 sequences. The most relevant results are the following: (1) North African sequences (haplogroup U6) present an overall frequency of 2.39%, and sub-Saharan sequences reach 3.83%, values that are, in both cases, much higher than those generally observed in Europe; and (2) there is a substantial geographic heterogeneity in the distribution of these lineages (haplogroup L being the most frequent in the south, whereas haplogroup U6 is generally more common in the north). The analysis of the observed diversity within each haplogroup strongly suggests that both were recently introduced (in historical times). Although for haplogroup U6 the documented event that is demographically compatible is the Islamic period (beginning of the 8th century to the end of the 15th century), for haplogroup L the most probable origin is the modern slave trade (mid 15th century to the end of the 18th century). However, the observed geographic structuring for one of the haplogroups does not fit the expected distribution provided by simplistic historical considerations. In fact, although for haplogroup L the north-south increasing frequency is corroborated by historical data, the opposite trend, observed for haplogroup U6, is more difficult to reconcile with the magnitude and time span of the Islamic political and cultural influence, which lasted longer and was more intense in the south. To clarify this conundrum, we need not only a substantial increase in the amount of mtDNA data (particularly for North Africa) but also new historical data and interpretations.

Africa South of the Sahara↗
PubMed2006

Hypervariable region structure and polymorphism of mtDNA from dental pulp and a family analysis.

Nucleotide sequences of the hypervariable region in the D-loop of mitochondrial DNA (mtDNA) were analyzed using DNA extracted from 140 old dental pulp samples. These sequences were compared with the sequence reported by Anderson et al. Nucleotide substitution in the HV1 region was identified at 77 positions. A C-to-T transition at position 16223 (C16223T) was most frequently detected (77.9%). Fourteen types of C-stretch sequence patterns were detected and the same sequence as Anderson had the highest frequency (57.9%). In the HV2 region, base transitions were identified at 56 positions. A263G was identified in all samples. Seven types of C-stretch were detected, but none had the same sequence as Anderson. In the HV3 region, base transitions were identified at 21 positions. T489C was most frequently identified (64.3%). Five types of C-stretch were detected, and the same sequence as Anderson accounted for 92.9%. The 140 samples were classified into 128 kinds by the sequence patterns of the HV region. Next, using the blood and oral mucosa epithelium from 23 subjects comprising four generations in a family line, the hereditary relationship of mtDNA was examined. All mtDNA types of the first-generation mother were infallibly inherited by the fourth generation.

Adult↗
PubMed1999

[Restriction polymorphism of the major noncoding region of mtDNA in the indigenous population of the TUVA republic].

Mitochondrial DNA sequence variation was examined in three rural populations of the indigenous inhabitants from the Tuva Republic. The frequencies of restriction sites within the D-loop region of mtDNA were determined. The three populations studied demonstrated similar patterns of mtDNA polymorphism. Like other Siberian populations, Tuvinians were characterized by high frequencies of the HaeIII 16517 and AspS9I (Cfr13I) 16516 restriction sites (about 75%). Moreover, in Tuvinians, a relatively low (71 to 81%) frequency of the KpnI 16129 restriction site was observed. The frequency of the mitotype differing from the Cambridge sequence by the HaeIII 16517 and KpnI 16129 sites in Tuvinians was higher than in Mongols and Russians. The features of mtDNA polymorphism point to the similarity between Tuvinians and other Siberian ethnic groups (Sel'kups in particular). This can be explained by the contribution of the Samoyed component, along with the Turkic and Mongoloid ones, to the formation of the Tuvinian ethnic group.

DNA, Mitochondrial↗
PubMed2000

Spatial and temporal stability of mtDNA haplogroup frequencies in native North America.

Mitochondrial DNA lineage frequencies in prehistoric Aleut, eastern Utah Fremont, Southwestern Anasazi, Pyramid Lake, and Stillwater Marsh skeletal samples from northwest Nevada and the Oneota of western Illinois are compared with those in 41 contemporary aboriginal populations of North America. The ancient samples range in age from 300 years to over 6,000 years. The results indicate that the prehistoric inhabitants of North America exhibit the same level of mtDNA variability as contemporary populations of the continent. Variation in modern mtDNA haplogroup frequencies is highly geographically structured, and the prehistoric samples exhibit the same geographic pattern of variation. This indicates that differentiation of regional patterns of mtDNA lineage variation occurred early in North American prehistory (much more than 2,000 years B.P.), has remained relatively stable since its origin, and was little influenced by the disruptions hypothesized for other genetic systems as a result of population declines and relocations at contact.

DNA, Mitochondrial↗
PubMed2000

MtDNA haplogroups in the populations of Croatian Adriatic Islands.

The number of previous anthropological studies pointed to very complex ethnohistorical processes that shaped the current genetic structure of Croatian island isolates. The scope of this study was limited to the general insight into their founding populations and the overall level of genetic diversity based on the study mtDNA variation. A total of 444 randomly chosen adult individuals from 32 rural communities of the islands of Krk, Brac, Hvar and Korcula were sampled. MtDNA HVS-I region together with RFLP sites diagnostic for main Eurasian and African mtDNA haplogroups were analysed in order to determine the haplogroup structure. The most frequent haplogroups were "H" (27.8-60.2%), "U" (10.2-24.1%), "J" (6.1-9.0%) and "T" (5.1-13.9%), which is similar to the other European and Near Eastern populations. The genetic drift could have been important aspect in history, as there were examples of excess frequencies of certain haplogroups (11.3% of "I" and 7.5% of "W" in Krk, 10.5% of "HV" in Brac, 13.9% of "J" in Hvar and 60.2% of "H" in Korcula). As the settlements on the islands were formed trough several immigratory episodes of genetically distant populations, this analysis (performed at the level of entire islands) showed greater genetic diversity (0.940-0.972) than expected at the level of particular settlements.

Adult↗
PubMed2001

[Sequence analysis of mtDNA 12S rRNA, tRNA(Leu(UUR)),tRNA(Ser(UCN))and 16S rRNA gene of 12 nonsyndromic inherited deafness pedigrees].

OBJECTIVE: To detect the relationship of mtDNA mutation with inherited deafness and the reason for pedigree's hypersensitivity to ototoxicity of aminoglycoside antibiotics(AmAn). METHODS: Pedigree investigations were conducted. The blood samples were obtained from 12 pedigrees, and DNA was extracted from the isolated leukocytes. After that, mtDNA fragments were amplified by PCR. The 1555(G), 3243(G) and 7445(G) mutations were detected by Alw 26 I, Apa I and Xba I restriction endonuclease digestion respectively, and then sequencing of 12S rRNA, tRNA(Leu(UUR)), tRNA(Ser(UCN))and 16S rRNA gene was performed. RESULTS: Restriction endonuclease digestion and sequence analysis showed that all the pedigrees carried mtDNA mutation, among them, 10 pedigrees carried 1555(G) mutation; 2 pedigrees, 7445(G) mutation; no pedigree was found to harbor the 3243(G) mutation. Sequence analysis of 16S rRNA gene showed that the mutations are 2230(G), 2230(AG), 2243(AG), 2230(AA). CONCLUSION: The pedigrees that carried 1555(G) or 7445(G) mutation showed hereditary or congenital hearing loss. The 1555(G) or 7445(G) mutation in association with 16S rRNA gene mutation led to pedigree's hypersensitivity to AmAn ototoxicity.

Base Sequence↗
PubMed2000

Intermittent hypoxia exposure prevents mtDNA deletion and mitochondrial structure damage produced by ischemia/reperfusion injury.

In the present study, polymerase chain reaction (PCR) was conducted to determine mtDNA(4834) deletion, and myocardial ultrastructure was visualized by electron microscope to see whether intermittent hypoxia (high altitude) adaptation exerts some action on mitochondria against ischemia/reperfusion injury. Myocardial ischemia/reperfusion in isolated perfused rat hearts induced severe damage to the ultrastructure of myocardial mitochondria and mtDNA4834 deletion down to 87.5% of normoxia rats. After the rats were exposed to intermittent hypoxia (5000 m; 6 h/d for 28 d), the myocardial structure was well reserved and mtDNA(4834) deletion dropped to 28.57%of control (P<0.05). It is suggested that intermittent hypoxia adaptation prevents mtDNA deletion, and preserves normal structure of mitochondria, which would be beneficial to the maintenance of normal mitochondrial function, and increases tolerance of myocardium against ischemia/reperfusion injury.

Animals↗
PubMedDate not supplied

MERRF/MELAS overlap syndrome in a family with A3243G mtDNA mutation.

Four members of a family were found to carry the A3243G mtDNA mutation. Clinical features varied from typical MELAS to myoclonic epilepsy to simple deafness without neurological signs. Several other members of the family had symptoms consistent with a mitochondrial disease. Muscle biopsy in 3 of the 4 patients showed the most prominent mitochondrial alterations with partial deficiency of cytochrome c oxidase in the case with the mildest phenotype. Mitochondrial DNA analysis detected a variable percentage of A3243G mutation, roughly correlating with the phenotype. The interesting feature of the family lies in the great intrafamilial variability of the severity of clinical expression, encompassing MELAS and MERRF features, associated with the A3243G mtDNA mutation. A search for the most common mtDNA mutations is recommended in all patients featuring incomplete MELAS or MERRF syndromes and in all familial cases presenting minimal clinical signs.

Adult↗
PubMed2002

Characterization of the Caucasian haplogroups present in the SWGDAM forensic mtDNA dataset for 1771 human control region sequences. Scientific Working Group on DNA Analysis Methods.

Currently, the Scientific Working Group on DNA Analysis Methods (SWGDAM) mtDNA dataset is used to infer the relative rarity of mtDNA profiles (i.e., haplotypes) obtained from evidence samples and for identification of missing persons. The Caucasian haplogroup patterns in this forensic dataset have been characterized using phylogenetic methods. The assessment reveals that the dataset is relevant and representative of U.S. and European Caucasians. The comparisons carried out were both the observation of variable sites within the control region (CR) and the selection of a subset of these sites, which partition the variation within human mtDNA control region sequences into clusters (i.e., haplogroups). The aligned sequence matrix was analyzed to determine both single nucleotide polymorphisms (SNPs) in a phylogenetic context, as well as to check and standardize haplogroup designations with a focus on determining the characters that define these groups. To evaluate the dataset for forensic utility, the haplogroup identifications and frequencies were compared with those reported from other published studies.

DNA, Mitochondrial↗