Mitochondrial Encephalomyopathy and Complex III Deficiency Associated with a Stop-Codon Mutation in the Cytochrome b Gene

Keightley, J. Andrew; Anitori, Roberto; Burton, Miriam D.; Quan, Franklin; Buist, Neil R. M.; Kennaway, Nancy G.

doi:10.1086/316900

Cited by 105 publications

(74 citation statements)

References 37 publications

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“…Although it is not known how OX-PHOS regulation differs in human tissues from cultured cells, the excess COX capacity was also estimated to be ϳ1.4 in isolated permeabilized muscle fibers (39). These data are consistent with the finding that the threshold for COX deficiency in the muscle of patients harboring mutations in COX genes is usually around 40%, as estimated by single fiber PCR/RFLP analyses of COX-deficient fibers (12,14,40). Thus, it is likely that a mild (i.e.…”

Section: Discussionsupporting

confidence: 90%

In Vivo Regulation of Oxidative Phosphorylation in Cells Harboring a Stop-codon Mutation in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit I

D'Aurelio¹,

Pallotti²,

Barrientos³

et al. 2001

Journal of Biological Chemistry

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The mechanisms that regulate oxidative phosphorylation in mammalian cells are largely unknown. To address this issue, cybrids were generated by fusing osteosarcoma cells devoid of mitochondrial DNA (mtDNA) with platelets from a patient with a stop-codon mutation in cytochrome c oxidase subunit I (COX I). The molecular and biochemical characteristics of cybrids harboring varying levels of mutated mitochondrial DNA were studied. We found a direct correlation between the levels of mutated COX I DNA and mutated COX I mRNA, whereas the levels of COX I total mRNA were unchanged. COX I polypeptide synthesis and steady-state levels were inversely proportional to mutation levels. Cytochrome c oxidase subunit II was reduced proportionally to COX I, indicating impairment in complex assembly. COX enzymatic activity was inversely proportional to the levels of mutated mtDNA. However, both cell respiration and ATP synthesis were preserved in cells with lower proportions of mutated genomes, with a threshold at ϳ40%, and decreased linearly with increasing mutated mtDNA. These results indicate that COX levels in mutated cells were not regulated at the transcriptional, translational, and post-translational levels. Because of a small excess of COX capacity, the levels of expression of COX subunits exerted a relatively tight control on oxidative phosphorylation.

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Section: Discussionsupporting

confidence: 90%

In Vivo Regulation of Oxidative Phosphorylation in Cells Harboring a Stop-codon Mutation in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit I

D'Aurelio¹,

Pallotti²,

Barrientos³

et al. 2001

Journal of Biological Chemistry

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“…Indeed, mutation G15242A (G165X) was recently identified in the muscle from this patient. 17 Analysis of these two patients shows therefore the great similarity of the molecular consequences between a nonsense mutation in the cytochrome b gene in humans and the cytochrome b null mutants described in yeast including the relative preservation of the cytochrome c 1 as compared to ISP. 36 ± 38 The molecular consequences of mutation T15197C (S151P) cannot be compared directly with yeast mutant because, to our knowledge, serine 151 has never been mutated in yeast.…”

Section: European Journal Of Human Geneticsmentioning

confidence: 93%

“…11,15,17,18 All these mutations were heteroplasmic ie they coexisted with a residual amount of wild-type mtDNA. Half of them led to a truncated cytochrome b protein.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of novel mutations in the human cytochrome b gene

et al. 2001

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The great variability of the human mitochondrial DNA (mtDNA) sequence induces many difficulties in the search for its deleterious mutations. We illustrate these pitfalls by the analysis of the cytochrome b gene of 21 patients affected with a mitochondrial disease. Eighteen different sequence variations were found, five of which were new mutations. Extensive analysis of the cytochrome b gene of 146 controls found 20 supplementary mutations, thus further demonstrating the high variability of the cytochrome b sequence. We fully evaluated the functional relevance of 36 of these 38 mutations using indirect criteria such as the nature of the mutation, its frequency in controls, or the phylogenetic conservation of the mutated amino acid. When appropriate, the mtDNA haplotype, the heteroplasmic state of the mutation, its tissue distribution or its familial transmission were also assessed. The molecular consequences of the mutations, which appeared possibly deleterious in that first step of evaluation, were evaluated on the complex III enzymological properties and protein composition using specific antibodies that we have generated against four of its subunits. Two original deleterious mutations were found in the group of seven patients with overt complex III defect. Both mutations (G15150A (W135X) and T15197C (S151P)) were heteroplasmic and restricted to muscle. They had significant consequences on the complex III structure. In contrast, only two homoplasmic missense mutations with dubious clinical relevance were found in the patients without overt complex III defect.

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“…Previously, complex III deficiency has been demonstrated in cases of cardiomyopathy, 3,4 exercise intolerance 5,6,7,14 or encephalomyopathy. 15 In these cases, the defect was essentially expressed in one tissue, and was shown to result from anomalies of mtDNA. The possibility of an mtDNA alteration in our patient was investigated by looking for frequent tRNA mutations, large-scale mtDNA rearrangements and Cyt b mutations.…”

Section: Discussionmentioning

confidence: 98%

The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

et al. 2004

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We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.

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Mitochondrial Encephalomyopathy and Complex III Deficiency Associated with a Stop-Codon Mutation in the Cytochrome b Gene

Cited by 105 publications

References 37 publications

In Vivo Regulation of Oxidative Phosphorylation in Cells Harboring a Stop-codon Mutation in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit I

In Vivo Regulation of Oxidative Phosphorylation in Cells Harboring a Stop-codon Mutation in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit I

Functional characterization of novel mutations in the human cytochrome b gene

The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

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