Mitochondrial DNA: does more lead to less?
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DNA, Mitochondrial↗
Biomedical subjects
I J Holt
Publications and source records attributed to I J Holt.
Maternally transmitted partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus.
Mitochondrial DNA from a 38 year old male with diabetes mellitus and features of mitochondrial dysfunction was analysed and shown to include a population with a partial duplication. The partially duplicated mitochondrial DNA molecules were evident in both muscle and blood. The region of mitochondrial DNA duplicated includes the origin of heavy strand replication, but not the light strand origin. This patient has features in common with other cases of partial direct tandem duplications and with a family which was reported to harbour a 10.4 kb mtDNA deletion. Initial restriction enzyme analysis of our case produced results consistent with a partial deletion of mitochondrial DNA. This leads us to propose that the rarity of reports of partial mitochondrial DNA duplications may stem in part from the classification of such mutants as partial deletions.
Adult↗
Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion.
We have studied cultured skin fibroblasts from a patient with a fatal mitochondrial disease manifesting soon after birth. These fibroblasts were found to grow only in the presence of pyruvate and uridine, a characteristic of cells lacking mtDNA (rho0 cells). Southern blot and PCR analyses confirmed that the patient's fibroblasts contained less than 2% of control levels of mtDNA. Biochemical analyses indicated that the activities of all the respiratory-chain enzymes were severely decreased in mitochondria isolated from these fibroblasts. In order to elucidate the underlying molecular defect, cell fusions were performed between enucleated fibroblasts from this patient and a human-derived rho0 cell line (rho0 A549.B2). The resulting cybrids were plated in medium lacking pyruvate and uridine, to select for the restoration of respiratory-chain function. Complementation was observed between the nuclear genome of the rho0 A549.B2 cells and the mtDNA of the patient's cells, restoring mtDNA levels and respiratory-chain function in the cybrid cells. These results indicate that mtDNA depletion in our patient is under the control of the nuclear genome.
Cell Fusion↗
Evidence for intramitochondrial complementation between deleted and normal mitochondrial DNA in some patients with mitochondrial myopathy.
Twenty-three patients with mitochondrial myopathies and mitochondrial DNA deletions in muscle were studied by means of deletion mapping and sequencing, histochemistry and polarography. Histochemistry showed significantly less focal cytochrome oxidase deficiency relative to number of ragged red fibres when the deletion did not involve reading frames for cytochrome oxidase subunits. Polarography in such patients showed defects exclusively involving complex I, in contrast to the others with larger deletions who generally had more diffuse respiratory chain defects. Analysis of other published histochemical data showed similar findings to our own. It is concluded that translation of a proportion of deleted mitochondrial DNAs occurs in at least some patients with mitochondrial DNA deletions, implying that deleted and normal mitochondrial genomes share transfer RNAs within mitochondria in such cases.
Base Sequence↗
Prenatal diagnosis of mitochondrial DNA8993 T----G disease.
We have previously described a family with a neurological syndrome comprising neurogenic muscle weakness, ataxia, retinitis pigmentosa, and variable sensory neuropathy, seizures, and mental retardation or dementia. This is associated with a heteroplasmic point mutation of mtDNA at bp 8993. The mother of a severely affected child underwent prenatal diagnosis in two further pregnancies. Analysis of chorionic villus samples showed a higher proportion of mutant mtDNA on both occasions, and this was reflected in the majority of fetal tissues, including brain and muscle. Prenatal diagnosis is a rational approach to the prevention of severe diseases caused by point mutations of mtDNA but is currently hampered by incomplete knowledge concerning the proportion of mutant mtDNA: its relationship to disease severity, how it may change during fetal and postnatal development, and its tissue distribution.
Child, Preschool↗
The molecular pathology of human respiratory chain defects.
Deletions of the mitochondrial genome were identified in 21 out of 58 patients (36 percent) with mitochondrial myopathies, 47 of whom had defects in the mitochondrial respiratory chain. In cases with Complex I defects, the deleted regions of mtDNA, were confined to structural genes encoding Complex I subunits but additionally involved the intervening tRNA genes and in one case included the large and small rRNA genes. In cases with more extensive loss of respiratory chain function, the deletions eliminated genes encoding subunits of Complexes I, IV and V, as well as several tRNAs. Complex I and Complex IV polypeptides were usually normal in deleted cases. This was in contrast to 7 out of 22 patients without detectable mtDNA deletions, who showed specific deficiencies of subunits encoded by nuclear genes. Further studies in one of these cases pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The genetic basis of the disease in 15 cases without detectable deletions or specific subunit deficiencies, remains unknown. The multiple biochemical abnormalities encountered in these cases would be consistent with more subtle alterations of the mitochondrial genome.
Chromosome Deletion↗
Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA.
A patient is described who has features of Pearson syndrome and who presented in the neonatal period with a hypoplastic anemia. He later developed hepatic, renal, and exocrine pancreatic dysfunction. At the age of 5 years he developed visual impairment, tremor, ataxia, proximal muscle weakness, external ophthalmoplegia, and a pigmentary retinopathy (Kearns-Sayre syndrome). Muscle biopsy confirmed the diagnosis of mitochondrial myopathy. Analysis of mtDNA from leukocytes and muscle showed mtDNA heteroplasmy in both tissues, with one population of mtDNA deleted by 4.9 kb. The deleted region was bridged by a 13-nucleotide sequence occurring as a direct repeat in normal mtDNA. Both Pearson syndrome and Kearns-Sayre syndrome have been noted to be associated with deletions of mtDNA; they have not previously been described in the same patient. These observations indicate that the two disorders have the same molecular basis; the different phenotypes are probably determined by the initial proportion of deleted mtDNAs and modified by selection against them in different tissues.
Anemia, Sideroblastic↗
The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies.
Some of the different molecular pathologies of respiratory-chain dysfunction in human mitochondrial myopathies will be reviewed in relation to the findings in 58 cases. Deletions of mitochondrial DNA were identified in 21 cases [36%]. There was some correlation between the sites of the deletion and the mitochondrial biochemistry in patients with defects of Complex I but not in cases with more extensive loss of respiratory chain activity. Complex I and Complex IV polypeptides were usually normal in deleted cases. Non-deleted cases, however, often showed specific subunit deficiencies which involved the products of both nuclear and mitochondrial genes. Immunoblots of respiratory-chain polypeptides in one case pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The pathogenic role of circulating autoantibodies to specific matrix proteins and the nature of the target antigens in two patients with mitochondrial encephalomyopathies and respiratory-chain dysfunction will also be discussed.
Autoantibodies↗
Mitochondrial DNA analysis in Parkinson's disease.
The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.
DNA Damage↗
Biochemical and molecular aspects of human mitochondrial respiratory chain disorders.
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Electron Transport Complex II↗
Mitochondrial myopathies: genetic defects.
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Amino Acid Sequence↗
Mitochondrial myopathies: clinical defects.
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Adolescent↗
A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.
A variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy occurred in four members of a family and was maternally transmitted. There was no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained two populations of mitochondrial DNA, one of which had a previously unreported restriction site for AvaI. Sequence analysis showed that this was due to a point mutation at nucleotide 8993, resulting in an amino acid change from a highly conserved leucine to arginine in subunit 6 of mitochondrial H(+)-ATPase. There was some correlation between clinical severity and the amount of mutant mitochondrial DNA in the patients; this was present in only small quantities in the blood of healthy elderly relatives in the same maternal line.
Adult↗
Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms.
Forty per cent of patients with mitochondrial myopathies, a diverse group of multisystem diseases predominantly affecting skeletal muscle and the brain, have large deletions of a proportion of muscle mitochondrial DNA (mt DNA). These appeared to be identical in 13 of 28 cases, contained within the region 8286-13595 bp. Analysis of the deletion junction in two cases showed a 13 nucleotide sequence which occurred in the normal genome as a direct repeat flanking the region deleted in the mutant mt DNAs. Mt DNA deletions may arise from recombination or slippage between short sequence repeats during replication.
Amino Acid Sequence↗
Molecular genetics of amyloid neuropathy in Europe.
The Portuguese type of familial amyloid polyneuropathy (FAP type I), a disabling autosomal dominant disorder with onset in early adult life, is caused by a point mutation in the transthyretin (TTR; previously known as prealbumin) gene. DNA analysis in thirteen European families (one British, two French, one Italian, one Greek, and eight Cypriot) showed that members of all those from Cyprus and Greece, and one from France, carried the FAP type I mutation. Patients from seven of these ten kindreds were not known to have a genetic disease before this study, which demonstrated the mutation in 16 of 43 clinically unaffected relatives. 2 of these were aged over 50 years. TTR gene analysis has useful applications in genetic counselling, including prenatal diagnosis, in identifying the cause of seemingly sporadic cases of amyloid neuropathy, and in epidemiological studies of FAP.
Adult↗
Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA.
Analysis of mitochondrial DNA (mtDNA) in muscle and blood from 72 patients with mitochondrial myopathy showed that 30 had major deletions of a variable proportion of muscle mtDNA. All of these 30 patients presented with progressive external ophthalmoplegia and limb weakness, and 8 had the additional features of the Kearns-Sayre syndrome. Of the 42 patients without detectable muscle mtDNA deletions, 10 had progressive external ophthalmoplegia and limb weakness, 2 had the Kearns-Sayre syndrome, 11 had limb weakness without extraocular involvement, and 19 had multisystem disorders predominantly affecting the central nervous system. Only 2 patients with mtDNA deletions had clinically affected relatives, compared with 10 of those without deletions. In the 4 patients with polarographic defects exclusively involving complex I (NADH coenzyme Q reductase), the deleted protein-coding genes were confined to those for complex I subunits. Thirteen other patients with apparently identical deletions had variable clinical and biochemical features. Immunoblots of complex I polypeptides from patients with deletions were either indistinguishable from controls or showed only a mild generalized decrease in all identifiable subunits.
Adult↗
Mitochondrial myopathies.
The mitochondrial myopathies give rise to a diverse group of clinical syndromes, variably involving skeletal muscle and the central nervous system, with onset in childhood or adult life. In vitro studies of mitochondrial metabolism have identified a variety of functional defects of the respiratory chain, predominantly affecting complex I or complex III in adults, and complex IV in children. The increased incidence of maternal, as opposed to paternal, transmission in familial mitochondrial myopathy has led to the suggestion that these disorders may be caused by mutations of mitochondrial (mt) DNA. This hypothesis is derived from observations that mtDNA encodes subunits of the respiratory chain proteins and is exclusively maternally transmitted. Analysis of muscle mtDNA shows two populations, one normal and the other deleted by up to nearly half its length, in about 40% of cases of mitochondrial myopathy. Only a single normal length population of mtDNA is seen in blood from these patients, and in blood and muscle from control subjects. Patients with muscle mtDNA deletions reported to date have all presented with progressive external ophthalmoplegia, including some with the Kearns-Sayre syndrome. They rarely have affected relatives. Deletions are not detected in cases of proximal myopathy alone, or those with adult onset syndromes predominantly affecting the central nervous system. There is no clear correlation between the deleted coding regions and the biochemical defects; even patients with seemingly identical muscle mtDNA deletions may be clinically and biochemically heterogeneous.
DNA, Mitochondrial↗
Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy.
Analysis of mitochondrial DNA from patients with Leber's hereditary optic neuropathy and their relatives showed that the previously reported mutation at base pair (bp) 11778, shown by loss of a recognition site for the restriction endonuclease SfaNI, was present in only four out of eight families. This mutation was associated with a poor prognosis for visual recovery, whereas four of five affected males without the 11778 bp mutation followed for four years or more had regained useful vision. All but one of the subjects showing the SfaNI site loss had a variable mixture of mutant and normal mitochondrial DNA in peripheral blood, and the relative proportions appeared to be correlated with the risk of developing or transmitting Leber's hereditary optic neuropathy.
Adult↗