Duplications of mitochondrial DNA in Kearns-Sayre syndrome

Abstract

mtDNA duplications were detectable in 10 of 10 patients with mtDNA deletions and Kearns-Sayre syndrome (KSS) and in none of 8 patients with chronic progressive external ophthalmoplegia (CPEO). Thus, duplications of mtDNA seem to be a distinctive feature of KSS, including patients where Pearson's syndrome is the first manifestation. Diabetes mellitus was identified in 4 of 7 patients with high or moderate levels of mtDNA duplications. The balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.

Rearrangements of Human Mitochondrial DNA (mtDNA): New Insights into the Regulation of mtDNA Copy Number and Gene Expression

“…Duplicated mtDNAs, although they may not be pathogenic in and of themselves, could still have pathogenic consequences if they are recombination intermediates that could give rise to deleted mtDNAs (Poulton et al, 1993(Poulton et al, , 1995, which are pathogenic. This is particularly relevant to those disorders in which duplicated mtDNAs, but not the corresponding deleted mtDNAs, have been detected, such as maternally inherited diabetes and deafness (Dunbar et al, 1993).…”

“…Partial deletions of mtDNA in these patients were first described in 1988 (Holt et al, 1988;Lestienne and Ponsot, 1988;Zeviani et al, 1988), followed soon thereafter by the identification of partial duplications of mtDNA (Poulton et al, 1989). It was determined later that deleted and duplicated mtDNAs coexist in a subset of KSS patients (Poulton et al, 1993(Poulton et al, , 1995Brockington et al, 1995). Besides KSS, clinical phenotypes associated with large-scale mtDNA rearrangements include renal tubulopathy, cerebellar ataxia, and diabetes mellitus (Rö tig et al, 1992); progressive external ophthalmoplegia, myopathy, and diabetes (Dunbar et al, 1993); diabetes and deafness (Ballinger et al, 1992(Ballinger et al, , 1994; and late-onset myopathy (Manfredi et al, 1997).…”

Maintenance of Human Rearranged Mitochondrial DNAs in Long-Term Cultured Transmitochondrial Cell Lines

“…Often, however, these patients also harbor a third mtDNA species-a partial duplication (dup-mtDNA)-as well (Poulton et al, 1989;Poulton et al, 1993;Poulton et al, 1994;Poulton et al, 1995;Schon et al, 1997). In all such "triplasmic" patients (i.e., containing wt-, ⌬-, and dup-mtDNAs), the two rearranged species are always topologically related: the dup-mtDNA can be thought of as being composed of a wt-mtDNA and a ⌬-mtDNA arranged head to tail (see example in Figure 1A), suggesting that the two rearranged species are generated through a common mechanism, or that one may be derived from the other (reviewed in Schon et al, 1997).…”

Identical large scale rearrangement of mitochondrial DNA causes Kearns-Sayre syndrome in a mother and her son

“…However, as no other tissue was investigated, it cannot be excluded that partially duplicated mtDNA species were present in extra-muscle organs, and notably in the oocytes of the affected mother. In our family, we do not know whether, as previously suggested, partially deleted species were generated from partially duplicated species [10][11][12][13] or, vice versa, the duplicated species were produced by recombination events between a partially deleted and a wild type mtDNA. Both mechanisms could indeed occur in the same cell population, and at the same time or at different times during the lifespan of a particular cell, tissue, or individual.…”