Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.99.5 (NADH dehydrogenase)
2,135 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular genetic analysis was performed in two autopsy-confirmed cases of early-onset Alzheimer's disease belonging to a large German pedigree [FAD2, according to the nomenclature of St. George-Hyslop, et al. (1987) Science 235:885-890]. The disease in this family has been linked to chromosome 14. As gene interactions are considered to influence the age of onset and tissue pathology in Alzheimer's disease, we have studied three candidate genes that could modify disease progression. In this study a new polymerase chain reaction (PCR) assay was established for apolipoprotein E genotyping in archival neuropathological tissue, exon 17 of the amyloid precursor protein gene was directly sequenced, and a candidate mutation site at nucleotide (nt) 5460 of the mitochondrial NADH dehydrogenase subunit gene ND2 was analyzed employing PCR followed by HphI digestion. Whereas no sequence variations were detected in exon 17APP or at nt5460 of mitochondrial DNA, the apolipoprotein E genotypes of the two cases differed. Neuropathological examination revealed a higher number of beta A4-positive amyloid plaques and a larger total tissue area covered by beta A4 deposits in the epsilon 3/epsilon 3 homozygote. In contrast, the number of cortical neurofibrillary tangles and the number of plaques with tau-positive neurites appeared to be higher in the epsilon 3/epsilon 4 heterozygote. Our findings support the view that the chromosome 14 genetic defect, rather than apolipoprotein E genotype, is the preeminent factor determining Alzheimer's disease pathology in this family.
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PMID:Apolipoprotein E genotype and neuropathological phenotype in two members of a German family with chromosome 14-linked early onset Alzheimer's disease. 852 99

The cause of nerve-cell death in sporadic Parkinson's disease remains unknown. Although environmental factors have been traditionally implicated in the etiology of Parkinson's disease, recent studies strongly suggest that there is a genetic contribution to this multifactorial disorder. We studied archival brain tissue from clinically and neuropathologically verified cases of Parkinson's disease, using nonradioactive cycle sequencing and restriction enzymatic analysis of polymerase chain reaction products. Twenty-one Parkinsonian brains with brain stem Lewy-bodies and 77 control brains were genotyped at two mitochondrial loci previously implicated in the etiology of neurodegenerative disease. In addition, genotyping was performed for two alleles of the debrisoquine 4-hydroxylase gene (CYP2D6). A heteroplasmic mtDNAG5460A missense mutation in the ND2 subunit gene of NADH dehydrogenase was three times more frequent in Parkinson cases (4/21) compared to controls (5/77). A homoplasmic mtDNAA4336G transition which alters the mitochondrial tRNAGln gene product was found in one Parkinson case. Frequencies of the CYP2D6G1934A and CYP2D6C2938T alleles were not significantly different between Parkinson cases and controls. Two Parkinsonian brains with high degrees of heteroplasmy for the ND2G5460A mutation and one CYP2D6C2938T homozygous case showed very high numbers of Lewy-bodies in the substantia nigra. The results of this study are in line with the concept that different genetic loci may be involved in Parkinson's disease susceptibility. They provide a hint that the ND2(5460) mutation, in combination with other factors, could play a role in disease pathogenesis in a subset of patients.
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PMID:Mitochondrial NADH dehydrogenase and CYP2D6 genotypes in Lewy-body parkinsonism. 872 26

There is increasing evidence for a role of defects of mitochondrial DNA in the etiology of neurodegenerative disorders such as Parkinson's and Alzheimer's disease as well as in normal aging. In several studies a biochemical defect of complex I of the respiratory chain (NADH dehydrogenase, EC 1.6.5.3) has been found in the substantia nigra of Parkinsonian brains. Thus, mutations of mitochondrial genes encoding subunits of complex I could contribute to the pathogenesis of Parkinson's disease. A heteroplasmic G5460A mutation affecting the ND2 subunit of NADH dehydrogenase was detected in several brains of patients with idiopathic Parkinson's disease. Since this mutation is heteroplasmic we were interested in the distribution of mutated and wild-type mitochondrial DNA in different brain areas. Relative levels of mutated DNA were quantified in a large number of anatomical regions using DNA extracted from formalin-fixed and paraffin-embedded brain tissue. DNA was amplified by the polymerase chain reaction and digested employing the restriction enzyme Hphl. The proportion of mutated DNA was determined by laser densitometry. In addition, genotype-phenotype analyses were performed on sections of the substantia nigra with the aid of an automated image analysis system. Ratios of mutant to wild-type DNA varied between 44% and 98%. However, there was no systematic relationship between mutated DNA ratios and ontogenetically related brain areas suggesting that the observed regional heterogeneity of mitochondrial DNA heteroplasmy is most likely due to random segregation during development. Therefore, tissue-specific differences in the sensitivity to pathogenic effects of the ND2(5460) mutation or the influence of additional susceptibility genes may be envisioned.
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PMID:Regional heterogeneity of mtDNA heteroplasmy in parkinsonian brain. 893 82

Phylogenetic relationships among Tibetan populations of the Bufo bufo species group are investigated using 1063 bases of mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), and ND2. The aligned sequences contain 181 phylogenetically informative characters across all taxa sampled. Two hypotheses for colonization of the Tibetan Plateau are tested. A vicariant hypothesis predicts monophyly of populations from high elevations. A dispersalist hypothesis predicts monophyly of populations in each of two river drainages (Yangtze and Yellow rivers), which requires nonmonophyly of populations from high elevations. Both hypotheses are rejected in favor of a third hypothesis that combines elements of vicariance and dispersal. The most parsimonious phylogenetic tree places the high-elevation species, B. andrewsi, as the sister taxon to the other Asian Bufo populations; these high-elevation populations are postulated to have had a vicariant origin approximately 5 million years before present. The high-elevation population recognized as B. minshanicus is nested within low-elevation populations of B. gargarizans and is suggested to have dispersed onto the Tibetan Plateau more recently.
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PMID:Phylogenetic relationships of toads in the Bufo bufo species group from the eastern escarpment of the Tibetan Plateau: a case of vicariance and dispersal. 947 97

Phylogenetic relationships within the Laudakia caucasia species group on the Iranian Plateau were investigated using 1708 aligned bases of mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNAGln, tRNAIle, tRNAMet, ND2, tRNATrp, tRNAAla, tRNAAsn, tRNACys, tRNATyr, and COI (subunit I of cytochrome c oxidase). The aligned sequences contain 207 phylogenetically informative characters. Three hypotheses for historical fragmentation of Laudakia populations on the Iranian Plateau were tested. In two hypotheses, fragmentation of populations is suggested to have proceeded along continuous mountain belts that surround the Iranian Plateau. In another hypothesis, fragmentation is suggested to have resulted from a north-south split caused by uplifting of the Zagros Mountains in the late Miocene or early Pliocene [5-10 MYBP (million years before present)]. The shortest tree suggest the later hypothesis, and statistical tests reject the other two hypothesis. The phylogenetic tree is exceptional in that every branch is well supported. Geologic history provides dates for most branches of the tree. A plot of DNA substitutions against dates from geologic history refines the date for the north-south split across the Iranian Plateau to 9 MYBP (late Miocene). The rate of evolution for this segment of mtDNA is 0.65% (0.61-0.70%) change per lineage per million years. A hypothesis of area relationships for the biota of the Iranian Plateau is generated from the phylogenetic tree.
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PMID:Phylogenetic relationships among Agamid lizards of the Laudakia caucasia species group: testing hypotheses of biogeographic fragmentation and an area cladogram for the Iranian Plateau. 975 22

Phylogenetic relationships among lizards of the families Anguidae, Anniellidae, Xenosauridae, and Shinisauridae are investigated using 2001 aligned bases of mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI (subunit I of cytochrome c oxidase), plus the origin for light-strand replication (O(L)) between the tRNA(Asn) and the tRNA(Cys) genes. The aligned sequences contain 1013 phylogenetically informative characters. A well-resolved phylogenetic hypothesis is obtained. Because monophyly of the family Xenosauridae (Shinisaurus and Xenosaurus) is statistically rejected, we recommend placing Shinisaurus in a separate family, the Shinisauridae. The family Anniellidae and the anguid subfamilies Gerrhonotinae and Anguinae each form monophyletic groups receiving statistical support. The Diploglossinae*, which appears monophyletic, is retained as a metataxon (denoted with an asterisk) because its monophyly is statistically neither supported nor rejected. The family Anguidae appears monophyletic in analyses of the DNA sequence data, and statistical support for its monophyly is provided by reanalysis of previously published allozymic data. Anguid lizards appear to have had a northern origin in Laurasia. Taxa currently located on Gondwanan plates arrived there by dispersal from the north in two separate events, one from the West Indies to South America and another from a Laurasian plate to Morocco. Because basal anguine lineages are located in western Eurasia and Morocco, formation of the Atlantic Ocean (late Eocene) is implicated in the separation of the Anguinae from its North American sister taxon, the Gerrhonotinae. Subsequent dispersal of anguine lizards to East Asia and North America appears to have followed the Oligocene drying of the Turgai Sea. The alternative hypothesis, that anguine lizards originated in North America and dispersed to Asia via the Bering land bridge with subsequent colonization of Europe and Morocco, requires a phylogenetic tree seven steps longer than the most parsimonious hypothesis. North African, European, and West Asian anguines were isolated from others by the rapid uplift of Tibet in the late Oligocene to Miocene. Phylogenetic analysis of evolutionary changes in the gene encoding tRNA(Cys) suggests gradual reduction of dihydrouridine (D) stems by successive deletion of bases in some lineages. This evolutionary pattern contrasts with the one observed for parallel elimination of the D-stem in mitochondrial tRNAs of eight other reptile groups, in which replication slippage produces direct repeats. An unusual, enlarged TpsiC (T) stem is inferred for tRNA(Cys) in most species.
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PMID:Molecular phylogenetics, tRNA evolution, and historical biogeography in anguid lizards and related taxonomic families. 1041 21

A well-supported phylogenetic hypothesis is presented for gekkonid lizards of the genus Teratoscincus. Phylogenetic relationships of four of the five species are investigated using 1733 aligned bases of mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI (subunit I of cytochrome c oxidase). A single most parsimonious tree depicts T. przewalskii and T. roborowskii as a monophyletic group, with T. scincus as their sister taxon and T. microlepis as the sister taxon to the clade containing the first three species. The aligned sequences contain 341 phylogenetically informative characters. Each node is supported by a bootstrap value of 100% and the shortest suboptimal tree requires 29 additional steps. Allozymic variation is presented for proteins encoded by 19 loci but these data are largely uninformative phylogenetically. Teratoscincus species occur on tectonic plates of Gondwanan origin that were compressed by the impinging Indian Subcontinent, resulting in massive montane uplifting along plate boundaries. Taxa occurring in China (Tarim Block) form a monophyletic group showing vicariant separation from taxa in former Soviet Central Asia and northern Afghanistan (Farah Block); alternative biogeographic hypotheses are statistically rejected. This vicariant event involved the rise of the Tien Shan-Pamir and is well dated to 10 million years before present. Using this date for separation of taxa occurring on opposite sides of the Tien Shan-Pamir, an evolutionary rate of 0.57% divergence per lineage per million years is calculated. This rate is similar to estimates derived from fish, bufonid frogs, and agamid lizards for the same region of the mitochondrial genome ( approximately 0.65% divergence per lineage per million years). Evolutionary divergence of the mitochondrial genome has a surprisingly stable rate across vertebrates.
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PMID:Vicariant patterns of fragmentation among gekkonid lizards of the genus Teratoscincus produced by the Indian collision: A molecular phylogenetic perspective and an area cladogram for Central Asia. 1041 26

Phylogenetic relationships among salamandrids of the "true" salamander clade are investigated using 2019 aligned base positions (713 parsimony informative) of 20 mitochondrial DNA sequences from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI (subunit I of cytochrome c oxidase), plus the origin for light-strand replication (O(L)) between the tRNA(Asn) and the tRNA(Cys) genes. Parsimony analysis produces a robust phylogenetic estimate for the relationships of the major groups of "true" salamanders. Strong support is provided for the sister taxon relationship of Chioglossa and Mertensiella caucasica and for the placement of Salamandra and Mertensiella luschani as sister taxa. These relationships suggest two vicariant events between Europe and Anatolia caused by the formation of seaways in the Mediterranean Basin. Molecular divergence indicates an Early Miocene separation of Chioglossa and M. caucasica and a Late Miocene separation of Salamandra and M. luschani. The traditional phylogenetic hypothesis of a monophyletic Mertensiella is statistically rejected, indicating that southwestern and northeastern Anatolian populations have separate historical biogeographic origins. Therefore, we recommend placement of M. luschani in the genus Salamandra. Within M. luschani, six highly divergent lineages showing 7.6 to 10.1% pairwise sequence divergence are identified. Tests using four-taxon subsamples suggest that these lineages diverged nearly simultaneously in the Late Miocene, approximately 6 to 8 million years ago, when extensive uplifting of Anatolia occurred in response to the Arabian collision.
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PMID:Molecular phylogenetics and historical biogeography among salamandrids of the "true" salamander clade: rapid branching of numerous highly divergent lineages in Mertensiella luschani associated with the rise of Anatolia. 1127 35

Phylogenetic relationships among frogs of the genus Rana from western North America are investigated using 2013 aligned bases of mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI (subunit I of cytochrome c oxidase), plus the origin for light-strand replication (O(L)) between the tRNA(Asn) and tRNA(Cys) genes. The aligned sequences contain 401 phylogenetically informative characters. A well-resolved phylogenetic hypothesis in which the Rana boylii species group (R. aurora, R. boylii, R. cascadae, R. muscosa, and R. pretiosa) is monophyletic is obtained. Molecular sequence divergence suggests that the R. boylii species group is approximately 8 million years old. The traditional hypothesis showing monophyly of the yellow-legged frogs (R. boylii and R. muscosa) is statistically rejected in favor of a hypothesis in which R. aurora, R. cascadae, and R. muscosa form a clade. Reanalyses of published nuclear ribosomal DNA restriction-site data and allozymic data support a monophyletic R. boylii group, but do not effectively resolve relationships among species within this group. Eight populations of R. muscosa form two major clades separated by a biogeographic break in the Sierra Nevada of California. This biogeographic break is broadly concordant with breaks found in four other amphibian and reptilian taxa. The two major clades within R. muscosa are estimated to have diverged approximately 2.2 million years before present. Each of these major clades contains two subgroups showing approximately 1.5 million years divergence, implicating climatic effects of Pleistocene glaciation in vicariance. The four distinct subgroups of R. muscosa separated by at least 1.4 million years of evolutionary divergence are suggested as potential units for conservation.
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PMID:Molecular phylogenetics of western North American frogs of the Rana boylii species group. 1128 98

The amounts of superoxide and hydrogen peroxide generated by mitochondria under physiological conditions can be enhanced by cellular stress. This study tested the hypothesis that the response to hemin-induced stress, which includes heme oxygenase-1 (HO-1) induction, predisposes to oxidative damage of mitochondrial DNA (mtDNA). Hepatic mitochondria from control, hemin-, and CO-exposed rats were incubated with tert-butyl hydroperoxide (tert-BH) or the NO donor 1,2,3,4-oxatriazolium, 5-amino-3- (3,4-dichlorophenyl)-chloride (GEA 3162). Mitochondrial total and oxidized glutathione (GSH and GSSG), total and free iron, and 8-oxo-7, 8-dihydro-2' deoxyguanosine (8-OHdG) were determined with and without oxidants. As expected, oxidation by tert-BH induced significant GSH depletion and increased amounts of free iron and 8-OhdG. Oxidant exposure rapidly produced a large mtDNA deletion involving the coding regions for cytochrome c oxidase (COX 1) and NADH dehydrogenase (ND1 and ND2). Hemin and CO greatly exacerbated susceptibility to the deletion of mtDNA by tert-BH, and this was attenuated by preincubation with GSH methyl ester. Analysis of mitochondria-associated proteins Bax and Bcl-xl in hemin- and CO-exposed rats showed significant responses, revealing interactions with apoptotic pathways. Thus, hemin-induced mitochondrial events sensitize a specific region of the mitochondrial genome to deletion, which is related to depletion of GSH and is not explained by effects of CO. This mtDNA damage is associated with altered expression of mitochondrial cell death proteins, thereby suggesting a novel mechanism for systemic or environmental pro-oxidants to influence apoptosis.
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PMID:Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure. 1182 50


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