Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome

Larsson, Nils‐Göran; Holme, Elisabeth; Kristiansson, Bengt; Oldfors, Anders; Tulinius, M.

doi:10.1203/00006450-199008000-00011

Cited by 282 publications

(135 citation statements)

References 6 publications

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“…This amplification is presumably due to a replicative advantage of the mtDNA molecules carrying them, as previously shown for pathogenetic point mutations (14) and for deletions (15,16). However, to account for the high proportion of mutated mtDNA found in muscle fibers, especially in the case of the A189G transition, one would have to assume multiple independent initiating events within mitochondria of different fibers.…”

Section: Discussionmentioning

confidence: 97%

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Wang

Michikawa

Mallidis

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

252

150

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The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects <40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations. R ecently, the discovery of an aging-dependent large accumulation of point mutations in the control region for mtDNA replication of human skin fibroblasts has been reported (1). Particularly striking was the demonstration, in a generally high proportion of molecules (up to 50%), of a T to G transversion at position 414 in the original Cambridge sequence (2), within the promoter for the synthesis of the RNA primer of mtDNA heavy (H)-strand synthesis (3) and for light (L)-strand transcription (4). This mutation was present in more than 50% of the individuals above 65 years of age and absent in younger individuals. In the present work, to investigate the occurrence of these aging-dependent mutations in other cell types, in particular, in postmitotic cells, a screening was carried out for the detection in human muscle of aging-related specific point mutations in the DLP4 and DLP6 segments of the main mtDNA control region, which were the segments previously found to carry the fibroblast mtDNA mutations (1). These two mtDNA segments correspond to one of the hypervariable portions of the main control region (5), and were chosen, for the purpose of analysis, as containing each a uniform melting domain (Y.M., unpublished data). They carry critical sequences for mtDNA replication (Fig. 1A). In particular, DLP4 contains the primary origin of H-strand mtDNA synthesis (O H1 ) (3), whereas DLP6 contains the promoter and start site for H-strand replication RNA...

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Section: Discussionmentioning

confidence: 97%

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Wang

Michikawa

Mallidis

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

252

150

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“…Preparation of DNA from lymphocytes was performed as described earlier (4) U of ApalI or 20U MnlI overnight. The resulting fragments were separated by electrophoresis in 8% polyacrylamide gels.…”

Section: ~Troduction Materials and Methodsmentioning

confidence: 99%

Is paternal mitochondrial DNA transferred to the offspring following intracytoplasmic sperm injection?

Houshmand

Holme

Hanson

et al. 1997

J Assist Reprod Genet

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“…When a mutant mitochondrial genome is propagated in the foetus its eventual representation and tissue distribution are presumed to be strongly influenced by its replication and segregation behaviour. For example, due to their smaller size del-mtDNA molecules may possess an inherent replicative advantage over wt-mtDNA molecules (Wallace 1989;Shoubridge et al 1990), at least in some cell types, resulting in their accumulation over time, as has been observed in a patient with KSS (Larsson et al 1990). The segregation behaviour of del-mtDNA can also depend on cell type (Bourgeron et al 1993), and differentiation status (Collombet et al 1996).…”

Section: Introductionmentioning

confidence: 93%

Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

et al. 1997

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Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome

Cited by 282 publications

References 6 publications

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Is paternal mitochondrial DNA transferred to the offspring following intracytoplasmic sperm injection?

Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

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