A TOPOISOMERASE-II CLEAVAGE SITE IS ASSOCIATED WITH A NOVEL MITOCHONDRIAL-DNA DELETION

Mitochondrial myopathies and encephalopathies can be caused by nucleot ide substitutions, deletions or duplications of the mitochondrial DNA (mtDNA) .In one such disorder, Kearns-Sayre Syndrome (KSS), large-scal e heteroplasmic mtDNA deletions are often found. We describe a 14-year -old boy with clinical features of KSS, plus some additional features. Analysis of the entire mitochondrial genome by the polymerase chain r eaction and Southern blotting revealed a 7864-bp mtDNA deletion, heter oplasmic in its tissue distribution. DNA sequencing established that t he deletion was between nucleotides 6238 and 14103, and flanked by a 4 -bp (TCCT) direct repeat sequence. Deletions between direct repeats ha ve been hypothesised to occur by a slipped-mismatching or illegitimate recombination event, or following the DNA cleavage action of topoisom erase II. Analysis of the gene sequence in the region surrounding the mtDNA deletion breakpoint in this patient revealed the presence of put ative vertebrate topoisomerase II sites. We suggest that direct repeat sequences, together with putative topoisomerase II sites, may predisp ose certain regions of the mitochondrial genome to deletions.