Mitochondrial oxidative phosphorylation defects in Parkinson's disease.
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Humans↗
Biomedical subjects
A Torroni
Publications and source records attributed to A Torroni.
Southeast Asian mitochondrial DNA analysis reveals genetic continuity of ancient mongoloid migrations.
Human mitochondrial DNAs (mtDNAs) from 153 independent samples encompassing seven Asian populations were surveyed for sequence variation using the polymerase chain reaction (PCR), restriction endonuclease analysis and oligonucleotide hybridization. All Asian populations were found to share two ancient AluI/DdeI polymorphisms at nps 10394 and 10397 and to be genetically similar indicating that they share a common ancestry. The greatest mtDNA diversity and the highest frequency of mtDNAs with HpaI/HincII morph 1 were observed in the Vietnamese suggesting a Southern Mongoloid origin of Asians. Remnants of the founding populations of Papua New Guinea (PNG) were found in Malaysia, and a marked frequency cline for the COII/tRNA(Lys) intergenic deletion was observed along coastal Asia. Phylogenetic analysis indicates that both insertion and deletion mutations in the COII/tRNA(Lys) region have occurred more than once.
Asia, Southeastern↗
Native American mitochondrial DNA analysis indicates that the Amerind and the Nadene populations were founded by two independent migrations.
Mitochondrial DNAs (mtDNAs) from 167 American Indians including 87 Amerind-speakers (Amerinds) and 80 Nadene-speakers (Nadene) were surveyed for sequence variation by detailed restriction analysis. All Native American mtDNAs clustered into one of four distinct lineages, defined by the restriction site variants: HincII site loss at np 13,259, AluI site loss at np 5,176, 9-base pair (9-bp) COII-tRNA(Lys) intergenic deletion and HaeIII site gain at np 663. The HincII np 13,259 and AluI np 5,176 lineages were observed exclusively in Amerinds and were shared by all such tribal groups analyzed, thus demonstrating that North, Central and South American Amerinds originated from a common ancestral genetic stock. The 9-bp deletion and HaeIII np 663 lineages were found in both the Amerinds and Nadene but the Nadene HaeIII np 663 lineage had a unique sublineage defined by an RsaI site loss at np 16,329. The amount of sequence variation accumulated in the Amerind HincII np 13,259 and AluI np 5,176 lineages and that in the Amerind portion of the HaeIII np 663 lineage all gave divergence times in the order of 20,000 years before present. The divergence time for the Nadene portion of the HaeIII np 663 lineage was about 6,000-10,000 years. Hence, the ancestral Nadene migrated from Asia independently and considerably more recently than the progenitors of the Amerinds. The divergence times of both the Amerind and Nadene branches of the COII-tRNA(Lys) deletion lineage were intermediate between the Amerind and Nadene specific lineages, raising the possibility of a third source of mtDNA in American Indians.
Asian People↗
Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.
Four new missense mutations have been identified through restriction analysis and sequencing of the mitochondrial DNAs (mtDNA) from Leber's hereditary optic neuropathy (LHON) patients who lacked the previously identified 11778 mutation. Each altered a conserved amino acid and correlated with the LHON phenotype in population and phylogenetic analyses. The nucleotide pair (np) 13708 mutation (G to A, ND5 gene) changed an alanine to a threonine and was found in 6/25 (24%) of non-11778 LHON pedigrees and in 5.0% of controls, the np 15257 mutation (G to A, cytochrome b gene) changed an aspartate to an asparagine and was found in 4 of the 13708-positive pedigrees and 0.3% of controls, the np 15812 mutation (G to A, cytochrome b gene) changed a valine to a methionine and was detected in two of the 15257-positive pedigrees and 0.1% of controls and the np 5244 mutation (G to A, ND2 gene) changed a glycine to a serine and was found in one of the 15812-positive patients and none of 2103 controls. The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b566 heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide. The 13708 and 15812 mutations changed moderately conserved amino acids. Haplotype and phylogenetic analysis of the four np 15257 mtDNAs revealed that all harbored the same rare Caucasian haplotype and that the np 13708, np 15257, np 15812 and np 5244 mutations were added sequentially along this mtDNA lineage. Since the percentage of sighted controls decreases as these mutations accumulate, it appears that they interact synergistically, each increasing the probability of blindness. The involvement of both mitochondrial complex I (np 5244, 11778, 13708) and complex III (np 15257, 15812) mutations in LHON indicates that the clinical manifestations of this disease are the product of an overall decrease in mitochondrial energy production rather than a defect in a specific mitochondrial enzyme.
Base Sequence↗
A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I.
A G-to-A transition at nucleotide pair (np) 7444 in the mtDNA was found to correlate with Leber hereditary optic neuropathy (LHON). The mutation eliminates the termination codon of the cytochrome c oxidase subunit I (COI) gene, extending the COI polypeptide by three amino acids. The mutation was discovered as an XbaI restriction-endonuclease-site loss present in 2 (9.1%) of 22 LHON patients who lacked the np 11778 LHON mutation and in 6 (1.1%) of 545 unaffected controls. The mutant polypeptide has an altered mobility on SDS-PAGE, suggesting a structural alteration, and the cytochrome c oxidase enzyme activity of patient lymphocytes is reduced approximately 40% relative to that in controls. These data suggest that the np 7444 mutation results in partial respiratory deficiency and thus contributes to the onset of LHON.
Amino Acid Sequence↗
American Indian prehistory as written in the mitochondrial DNA: a review.
Native Americans have been divided into three linguistic groups: the reasonably well-defined Eskaleut and Nadene of northern North America and the highly heterogeneous Amerind of North, Central, and South America. The heterogeneity of the Amerinds has been proposed to be the result of either multiple independent migrations or a single ancient migration with extensive in situ radiation. To investigate the origin and interrelationship of the American Indians, we examined the mitochondrial DNA (mtDNA) variation in 87 Amerinds (Pima, Maya, and Ticuna of North, Central, and South America, respectively), 80 Nadene (Dogrib and Tlingit of northwest North America and Navajo of the southwest North America), and 153 Asians from 7 diverse populations. American Indian mtDNAs were found to be directly descended from five founding Asian mtDNAs and to cluster into four lineages, each characterized by a different rare Asian mtDNA marker. Lineage A is defined by a HaeIII site gain at np 663, lineage B by a 9-bp deletion between the COII and tRNA(Lys) genes, lineage C by a HincII site loss at np 13259, and lineage D by an AluI site loss at np 5176. The North, Central, and South America Amerinds were found to harbor all four lineages, demonstrating that the Amerinds originated from a common ancestral genetic stock. The genetic variation of three of the four Amerind lineages (A, C, and D) was similar with a mean value of 0.084%, whereas the sequence variation in the fourth lineage (B) was much lower, raising the possibility of an independent arrival. By contrast, the Nadene mtDNAs were predominantly from lineage A, with 27% of them having a Nadene-specific RsaI site loss at np 16329. The accumulated Nadene variation was only 0.021%. These results demonstrate that the Amerind mtDNAs arose from one or maybe two Asian migrations that were distinct from the migration of the Nadene and that the Amerind populations are about four times older than the Nadene.
Asia↗
Mitochondrial tRNA(Thr) mutations and lethal infantile mitochondrial myopathy.
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DNA, Mitochondrial↗
Two additional MspI RFLPs revealed by MC.34 (D2S63).
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Chromosome Mapping↗
Mitochondrial oxidative phosphorylation defects in Parkinson's disease.
Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.
Adult↗
Mitochondrial DNA polymorphisms among Hindus: a comparison with the Tharus of Nepal.
The polymorphisms of mitochondrial DNA for the restriction enzymes HpaI, BamHI, HaeII, MspI, AvaII and HinecII were studied in a sample of 79 Hindus, 45 from New Delhi (India) and 34 from Terai (Nepal), both to characterize another Caucasian population and to investigate some possible Hindu component in the genetic structure of the Tharus, a Nepalese population, the anthropological position of which is still disputed. 1. A new BamHI polymorphism was detected: about 5% of the Hindu mtDNAs have lost the site at 14258 bp and lack any BamHI site. Once again a BamHI polymorphism was found in a Caucasian population. 2. New site mutations were found to yield morphs previously described (MspI-7, AvaII-18). 3. Variant morphs for two different enzymes were found due to a shared mutation (morphs BamHI-0/AvaII-30 and morphs MspI-7Hindu/AvaII-18Hindu). 4. Comparison between Hindu and Tharu data does not show any evidence of a specific Indian component in the Tharu genetic structure and allows us to conclude that Tharus are clearly differentiated from modern Hindus.
Adult↗
Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes.
Neoplastic transformation was found to have a marked effect on the expression of nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) genes. Examining three pairs of human diploid fibroblasts and their SV 40-transformed counterparts revealed that mRNAs for the nuclear-encoded ATP synthase beta and the adenine nucleotide translocator (ANT) isoform 1 and 2 genes were markedly induced, whereas the mRNA for the ANT isoform 3 gene remained unchanged. The mRNA levels for the mtDNA-encoded 12 S rRNA, ND2, ATPase6+8, COIII, ND5+6, and Cytb genes were also increased, whereas the mtDNA number declined. Similar analysis of a cervical carcinoma (HeLa), fibrosarcoma (HT1080), and an Epstein-Barr virus (EBV)-transformed lymphoblastoid line (EBV-L) revealed that all three ANT isoforms were also expressed in these cells. Hence, changes in the expression of OXPHOS genes may be a common feature of transformed cells.
Base Sequence↗
Y chromosome DNA polymorphisms in human populations: differences between Caucasoids and Africans detected by 49a and 49f probes.
Several Y-specific TaqI fragments are recognized by 49a and 49f probes in human male DNA digests. The occurrence of polymorphic variations in six of these fragments (A, B, C, D, F and I) has recently been reported, providing a potentially powerful tool for the study of the population genetics of the Y chromosome. The 49a-49f/TaqI polymorphisms were studied in 121 Africans (Senegal and Cameroon) and 125 Caucasians (Italy). In addition to the variability described already, four new bands were observed. Moreover, three patterns were found in which bands constantly present so far (G, O and H-P-R) were missing. At variance with previously reported findings, the coexistence of two different fragments of the same 'allelic' series (A or D) was frequently observed in the Italian sample (10.4%). For some of these 'double-banded' patterns their holoandric transmission could be demonstrated by family studies. In the light of these new findings, the hypothesis of A or D fragments being allelic forms, as advanced by the authors who first described these polymorphisms, has to be reconsidered. A total of 34 haplotypes were encountered, 22 of which are new. The Africans tested all lack C and D fragments. Moreover, about 80% of them are characterized by a band, A1, not present in the Italian group. The combination of A1C0D0 could therefore be a powerful genetic marker of paternal African ancestry. This combination occurs in five haplotypes, one of which, haplotype IV, accounts for 68% of the African sample. In contrast with the results of the mtDNA analysis on the same population samples, the degree of variability displayed by the Y chromosome sequences appears to be much lower in Africans than in Caucasians.
Africa↗
Mitochondrial DNA polymorphisms in Italy. III. Population data from Sicily: a possible quantitation of maternal African ancestry.
mtDNA polymorphisms were studied in a sample of 90 individuals of the Sicilian population using six restriction enzymes: HpaI, BamHI, HaeII, MspI, AvaII and HincII. (1) Three new patterns, for MspI, AvaII and HincII, have been detected. (2) At least two different mutations were found to account for both the AvaII morph 3 and the AvaII morph 9 as in many other Caucasian groups so far examined. (3) Seventeen types were found; of these six are new. The frequency (54.5%) of type 1-2 (2.1.1.1.1.2) is lower than in the rest of Italy whereas those of type 6-2 (2.1.2.1.1.2) (10.0%) and type 18-2 (2.3.1.4.9*.2) (12.2%) lie at the upper level of the Italian range. The 18-derivative, type 57-2 (2.3.1.4.13*.2), which is consistently found in all Italian samples, is present also among Sicilians with an incidence of 2.2%. (4) Of particular interest is that the HpaI-3/AvaII-3 complex, which is unique to groups of African ancestry, was found in Sicily at a frequency of 4.4%. For the first time an estimate of the amount of gene flow from Blacks to the Sicilian gene pool could be obtained.
Africa↗
Isolation and mapping of a polymorphic DNA sequence (lambda MC.34) on chromosome 2 [D2S63].
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Chromosome Mapping↗
Mitochondrial DNA polymorphisms in Italy. II. Molecular analysis of new and rare morphs from Sardinia and Rome.
A molecular analysis of morphs found in a previous survey of mtDNA restriction enzyme polymorphisms in Italy revealed that different site changes can give similar patterns and that the same mutation can yield variant morphs for apparently unrelated enzymes. 1. Alternative site variations were found to yield restriction fragment patterns resembling HpaI morph 4, HaeII morph 5 and AvaII morph 2. 2. A strong association was observed between the BamHI morph 3 (gain of site a) and the AvaII morph 9 and its derivatives (loss of site d). This association appears to result from an A to G transition at base pair (bp) 13,368 which simultaneously creates a new BamHI site and abolishes an AvaII site. On the other hand, the loss of the AvaII site d, which in Italy was only found in the above-mentioned association, does not always produce a new BamHI site, as observed in other Caucasian groups. Similarly, the BamHI morph 2 (gain of site b) was always found to be associated with AvaII morphs lacking site f. An A to G transition at bp 16,391 was shown to account for both changes. As in the previous case, the converse is not true. Hence, these data show that AvaII sites d and f were lost in more than one way and one of these seems to be typical of Caucasians. 3. The variation producing BamHI-3/AvaII-9 and derivatives is preferentially associated with MspI morph 4 but this is not a product of a shared mutation. Hence, this association must be the result of the linkage disequilibrium due to the maternal inheritance of mtDNA and lack of recombination. 4. The high frequency of the combination BamHI-3/AvaII-9 and derivatives with MspI-4 found in Italy (29 subjects out of 229 analysed) can best be explained by diffusion of the relevant haplotype rather than by repeated mutational events. 5. The phylogeny trees of all mtDNA morphs so far described and of mtDNA types in Caucasians have been revised taking into account both the inter- and the intra-morph heterogeneity detected by this analysis.
Child↗
Genetic studies on the Senegal population. I. Mitochondrial DNA polymorphisms.
The mtDNA of 186 Senegalese, mainly Wolof and Peuls, were analyzed by means of six restriction enzymes: HpaI, BamHI, HaeII, MspI, AvaII, and HincII. Two of the HpaI, one of the HaeII, two of the MspI, and one of the AvaII morphs had not been described before. The only enzymes which enabled Wolof and Peuls to be differentiated were HincII and, to a lesser extent, HaeII. Important differences emerge in the comparison of Senegalese with Bantu of South Africa and with Bushmen, the only other Africans who, as far as we know, were studied for the same genetic markers. Though Senegalese mtDNAs display typical African features (presence and frequency of HpaI morph 3 and high incidence of AvaII morph 3), the distribution of MspI and AvaII patterns markedly differentiates Senegalese from the others. The phylogeny of mtDNA types in Africa well portrays how the three African groups are clearly distinguishable genetic entities. Bushmen lie at one end of the range of variability, Senegalese being at the other end but still fairly closely related to Bantu. The information provided by individual restriction enzymes to the distinction among the three major ethnic groups is reviewed and discussed.
Black People↗
The pH dependence of pre-steady-state and steady-state kinetics for the papain-catalyzed hydrolysis of N-alpha-carbobenzoxyglycine p-nitrophenyl ester.
Pre-steady-state and steady-state kinetics of the papain (EC 3.4.22.2)-catalyzed hydrolysis of N-alpha-carbobenzoxyglycine p-nitrophenyl ester (ZGlyONp) have been determined between pH 3.0 and 9.5 (I = 0.1 M) at 21 +/- 0.5 degrees C. The results are consistent with the minimum three-step mechanism involving the acyl X enzyme intermediate E X P: (Formula: see text). The formation of the E X S complex may be regarded as a rapid pseudoequilibrium process; the minimum values for k+1 are 8.0 microM-1 s-1 (pH less than or equal to 3.5) and 0.40 microM-1 s-1 (pH greater than 6.0), and that for k-1 is 600 s-1 (pH independent). The pH profile of k+2/Ks (= kcat/Km; Ks = k-1/k+1) reflects the ionization of two groups with pK' values of 4.5 +/- 0.1 and 8.80 +/- 0.15 in the free enzyme. The pH dependence of k+2 and k+3 (measured only at pH values below neutrality) implicates one ionizing group in the acylation and deacylation step with pK'' values of 5.80 +/- 0.15 and 3.10 +/- 0.15, respectively. As expected from the pH dependences of k+2/Ks (= kcat/Km) and k+2, the value of Ks changes with pH from 7.5 X 10(1) microM (pH less than or equal to 3.5) to 1.5 X 10(3) microM (pH greater than 6.0). Values of k-2 and k-3 are close to zero over the whole pH range explored (3.0 to 9.5). The pH dependence of kinetic parameters indicates that at acid pH values (less than or equal to 3.5), the k+2 step is rate limiting in catalysis, whereas for pH values higher than 3.5, k+3 becomes rate limiting. The observed ionizations probably reflect the acid-base equilibria of residues involved in the catalytic diad of papain, His159-Cys25. Comparison with catalytic properties of ficins and bromelains suggests that the results reported here may be of general significance for cysteine proteinase catalyzed reactions.
Catalysis↗
The p12f2/TaqI Y-specific polymorphism in three groups of Italians and in a sample of Senegalese.
The TaqI/p12f2 Y-specific RFLP was studied in 258 Italians (69 from North, 74 from Centre-South and 115 from Southern Sardinia) and in 65 Senegalese. The two allelic fragments of 10 and 8 kb characterizing this polymorphism were both found in the Italians but only the 10 kb band was found among the Senegalese. The observed frequency of the 8 kb allele was 32.4% in Central-Southern Italians, 17.4% in Northern Italians and 13.0% in Southern Sardinians. The last figure is significantly lower than that (34.3%) previously reported for a smaller sample of the same population.
Alleles↗