An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region

Abstract

Deletions of muscle mitochondrial DNA (mtDNA) have recently been found in patients with mitochondrial myopathy. However, as most of the described cases were sporadic, and individual deletions involved different portions of mtDNA, the mechanism(s) producing the molecular lesions, as well as their mode of transmission, remain unclear. By studying families with mtDNA heteroplasmy, valuable information can be obtained about the role of inheritable factors in the pathogenesis of these disorders. We have studied four members of a family with autosomal dominant mitochondrial myopathy. Multiple deletions, involving the same portion of muscle mtDNA, were identified in all patients. Sequence analysis of the mutant mtDNAs, performed after DNA amplification by the polymerase-chain reaction showed that all the deletions start within a 12-nucleotide stretch at the 5' end of the D-loop region, a site of active communication between the nucleus and the mtDNA. The data indicate that a mutation of a nuclear-coded protein can destroy the integrity of the mitochondrial genome in a specific, heritable way.

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

“…It is demonstrated that the disorder of mtDNA can be induced by the defects of nuclear DNA [46]. Another putative mechanism is associated with reactive oxygen species (ROS).…”

Regulation of mitochondrial DNA content and cancer

“…In 1989, Zeviani and colleagues described autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletion, the first of several diseases attributed to defects of nuclear DNA leading to the disorder of mtDNA (Zeviani et al, 1989). Mutations in the mitochondrial proteins adenine nucleotide translocator 1 (ANT1) (Kaukonen et al), Twinkle (Spelbrink et al) and polymerase γ (Van Goethem et al) have been found to cause autosomal dominant progressive external ophthalmoplegia with multiple deletion of mtDNA.…”

Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse

“…2 Severe cases of mitochondrial myopathy can present with progressive external ophthalmoplegia (PEO), caused by paralysis of the extraocular eye muscles. 3 One of the best characterized causes of mitochondrial PEO is mutations in the nuclear DNA (nDNA)-encoded gene for the heart-muscle isoform of the adenine nucleotide translocator (Ant1) gene. 4 The ANTs export ATP generated by OXPHOS out across the mitochondrial inner membrane in exchange for cytosolic ADP, and thus are the main modulators of energy flux in the aerobic cell.…”