Abstract
Previous studies have suggested that some patients with large-scale mitochondrial DNA (mtDNA) deletions also presented a heteroplasmic 260 bp tandem duplication in the mtDNA D-loop region. Such duplications were observed not only in patients with mitochondrial pathology but also in aged subjects. However, the percentage of duplicated mtDNA did not exceed a few per cent of the total mtDNA, except in one example where it reached 30%. We report here another type of 200 bp duplication in the mtDNA D-loop region that, instead of being associated with a large-scale deletion, is correlated to the presence of a point mutation in the cytochrome b gene. The 200 bp duplication concerned up to 95% of the total mtDNA of some muscle mitochondria and was absent from the patient lymphocyte DNA. The percentages of the 200 bp duplication and that of the cytochrome b mutation were relatively close in whole muscle as well as in single muscle fibres, suggesting a correlation between the mutation and the duplication. This duplication could also be detected by PCR in two other patients with mitochondrial disorders but without known deletion or mtDNA mutation. These data suggest that the accumulation of these small duplications in the mtDNA D-loop could be indicative of the presence of other defects of the mtDNA which would damage the respiratory chain function. These deficiencies would induce the generation of small duplications in the D-loop.
Highlights
A heteroplasmic tandem duplication of low abundance with a size of ∼260 bp in the D-loop of human mitochondrial DNA was first observed by Brockington et al (1)
This study suggested that the 260 bp tandem duplication correlated with haplogroup I and with the insertion of Cs, but not with large mitochondrial DNA (mtDNA) deletions
We show that a 200 bp tandem duplication [type IX, according to Wei et al (8)] can exist at a much higher percentage than previously expected
Summary
A heteroplasmic tandem duplication of low abundance with a size of ∼260 bp in the D-loop of human mitochondrial DNA (mtDNA) was first observed by Brockington et al (1) It was found in patients bearing large-scale deletions in their mtDNA. Torroni et al (4) identified a tandem duplication similar to that of 260 bp in normal individuals belonging to a particular Caucasian mtDNA haplogroup (haplogroup I) These subjects harboured inserted stretches of [2,3,4,5,6] cytosines (Cs) between nucleotides 568 and 573 [mtDNA numbering being according to the Cambridge sequence (5)]. None of the 30 patients bearing muscle mtDNA deletions exhibits the 260 bp duplication in the study of Manfredi et al (6) These authors identified this duplication in a 58-year-old man with a late-onset slowly progressive mitochondrial myopathy. This could apply to any type of respiratory chain deficiency whether the genetic origin of the deficiency be a deletion or a point mutation in the mtDNA
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