Report of the committee on human mitochondrial DNA

Wallace, Douglas C.; Lott, Marie T.; Torroni, Antonio; Shoffner, John M.; Chang, E.; Malik, S.

doi:10.1159/000133724

Cited by 63 publications

(44 citation statements)

References 40 publications

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“…Given the high mutation rate and the great intraspecific variability of mtDNA, it is difficult to distinguish between pathogenic and nonpathogenic point mutations. The number of putatively pathogenic mtDNA mutations reported in the scientific journals has steadily increased in the recent past, making a thorough investigation of the normal variability of human mitochondrial genome as necessary as the identification oftrue or consensus mutations (14)(15)(16)(17). There is general agreement that the pathogenicity ofa given mtDNA mutation should be based on the following criteria ( 18) all cybrid clones contain the same nuclear genotype ofthe host rho' cell line, mutations in the nuclear genes of the proband are ruled out.…”

Section: Methodsmentioning

confidence: 99%

Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy.

et al. 1994

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We studied the physiometabolic effects of a mitochondrial DNA (mtDNA) heteroplasmic point mutation, the A Gtransition associated with maternally inherited myopathy and cardiomyopathy. To eliminate the possible influence of the autochthonous nuclear gene set, we fused myoblast-derived cytoplasts of a patient with a human tumoral cell line deprived of mtDNA (Rho0). The presence and amount of the mutant G3260 vs the wild-type A326" were measured by solid phase minisequencing. We observed a marked reduction of the percentage of mutant mtDNA in the culture system compared with that measured in the donor's muscle biopsy, suggesting the presence of negative selection against the mutation. Furthermore, stable mitotic segregation of the two mtDNA populations was observed in 18 of 19 transformant clones, suggesting the presence of intraorganelle and possibly intracellular homoplasmy in the precursor cells of the donor. Several indexes of mtDNA-related respiratory capacity, including oxygen consumption, complex I-and complex IV-specific activities, and lactate production, were markedly abnormal in the clones containing a high proportion of mutant mtDNA, as compared with those containing homoplasmic wild-type mtDNA, possibly because of impaired mitochondrial protein synthesis. We conclude that (a) the A -G31 transition is indeed responsible for the mitochondrial disorder identified in the donor patient, and (b) transformant cybrid system gives direct evidence of the mitochondrial origin of a genetic disorder and should be adopted for the evaluation of the pathogenic potential of the mtDNA mutations. (J. Clin.

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Section: Methodsmentioning

confidence: 99%

Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy.

et al. 1994

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“…Furthermore, the time of onset of LHON differs intrafamilially. To follow the idea that interacting LHON mtDNA point mutations [4,5] would perhaps explain some of these variations, we have investigated a German LHON family with respect to the 10 LHON-associated mutations reported so far [2]. All 10 family members under study carry the same LHON point mutation pattern independently of whether or not they are clinically affected.…”

Section: Discussionmentioning

confidence: 99%

“…The disease is associated with defined mutations of the mitochondrial DNA (mtDNA) [2]. About 50-80% of LHON patients can be attributed to a G-to-A transition mutation at position 11,778 in the ND4 subunit gene of complex I of the respiratory chain [3].…”

Section: Introductionmentioning

confidence: 99%

“…About 50-80% of LHON patients can be attributed to a G-to-A transition mutation at position 11,778 in the ND4 subunit gene of complex I of the respiratory chain [3]. For the remainder of the LHON patients not carrying this mutation several other mutations have been described [2]. In LHON families, usually both clinically affected and unaffected family members carry the mt genetical defect.…”

Section: Introductionmentioning

confidence: 99%

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No genetic differences between affected and unaffected members of a German family with Leber's hereditary optic neuropathy (LHON) with respect to ten mtDNA point mutations associated with LHON

Gerbitz¹,

Paprotta²,

Obermaier-Kusser³

et al. 1992

FEBS Letters

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In order to investigate possible synergistic influences of different mtDNA mutations on penetrance and severity of Leber's hereditary optic neuropathy (LHON), a large German LHON pedigree is characterized with respect to 10 different mutations associated with LHON. All members of the family carry three different mtDNA mutations (at nucleotide 4,216, 11,778 and 13,708) in a homoplasmic form, regardless of whether or not they are clinically affected. Testing for another 7 mutations reveals negative results in all family members. Hence, the variable disease expression of the family members cannot be explained by varying combinations of LHON‐associated mtDNA mutations.

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“…These defects take the form of either point mutations or rearrangements, such as deletions and duplications. Point mutations can occur in either the RNA or protein encoding genes, although the former are much more common (4). Most mtDNA mutations are heteroplasmic (the presence of both mutated and wildtype mtDNA) with a biochemical defect and clinical phenotype only apparent when mutant mtDNA levels are high (5-7).…”

Section: Introductionmentioning

confidence: 99%

SCID mice containing muscle with human mitochondrial DNA mutations. An animal model for mitochondrial DNA defects.

Clark¹,

Watt²,

Lightowlers³

et al. 1998

J. Clin. Invest.

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Defects of the mitochondrial genome are important causes of disease. Despite major advances in our investigation of patients, there is no effective therapy. Progress in this area is limited by the absence of any animal models in which we can evaluate treatment. To develop such a model we have injected human myoblasts into the tibialis anterior of SCID mice after inducing necrosis. After injection of normal human myoblasts, regenerating fibers expressed human ␤ -spectrin, confirming they were derived from fusion of human myoblasts. The stability of the muscle fibers was inferred by demonstrating the formation of motor end plates on the regenerating fibers. In addition, we show the presence of human cytochrome c oxidase subunit II, which is encoded by the mitochondrial genome, in the regenerated fibers. After injection of human myoblasts containing either the A8344G or the T8993C heteroplasmic mitochondrial DNA mutations, human ␤ -spectrin positive fibers were found to contain the mutation at a similar level to the injected myoblasts. These studies highlight the potential value of this model for the study of mitochondrial DNA defects. ( J. Clin. Invest. 1998. 102:2090-2095.)

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Report of the committee on human mitochondrial DNA

Cited by 63 publications

References 40 publications

Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy.

Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy.

No genetic differences between affected and unaffected members of a German family with Leber's hereditary optic neuropathy (LHON) with respect to ten mtDNA point mutations associated with LHON

SCID mice containing muscle with human mitochondrial DNA mutations. An animal model for mitochondrial DNA defects.

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