A Direct Repeat Is a Hotspot for Large-Scale Deletion of Human Mitochondrial DNA

TLDR

Kearns‑Sayre syndrome and progressive external ophthalmoplegia are neuromuscular disorders in which most KSS and about half of PEO patients exhibit large mitochondrial DNA deletions, including a common 5‑kb deletion present in over one‑third of cases. The common deletion is bounded by a perfect 13‑base pair direct repeat, indicating that homologous recombination can delete large mitochondrial segments in mammals and contributes to these myopathies.

Abstract

Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia (PEO) are related neuromuscular disorders characterized by ocular myopathy and ophthalmoplegia. Almost all patients with KSS and about half with PEO harbor large deletions in their mitochondrial genomes. The deletions differ in both size and location, except for one, 5 kilobases long, that is found in more than one-third of all patients examined. This common deletion was found to be flanked by a perfect 13-base pair direct repeat in the normal mitochondrial genome. This result suggests that homologous recombination deleting large regions of intervening mitochondrial DNA, which previously had been observed only in lower eukaryotes and plants, operates in mammalian mitochondrial genomes as well, and is at least one cause of the deletions found in these two related mitochondrial myopathies.