Walsh & Hoyt: Multiple Deletions of mtDNA in Autosomal-Dominant and Autosomal-Recessive Ophthalmoplegia

Autosomal-dominant and autosomal-recessive ophthalmoplegias are associated with multiple deletions of mtDNA. These deletions occur at multiple sites, involving a large portion of mtDNA, and most of them seem to be flanked by direct sequence repeats, shown to be ""hot spots"" in the case of single large deletions. The mutations map to sites on the nuclear genome that influence mtDNA replication or the size of nucleotide pools that support replication. Dominant mutations have been identified in genes encoding (a) mtDNA polymerase gamma (POLG), the sole polymerase responsible for mtDNA replication, (b) Twinkle, a putative helicase protein that may unwind mtDNA during replication, and (c) adenine nucleotide translocator (ANT1), which influences the size of ATP and ADP pools within mitochondria by controlling the transport of these nucleotides across the inner mitochondrial membrane. An autosomal-recessive mutation is associated with the gene encoding thymidine phosphorylase (TP), which is responsible for the thymidine salvage pathway in mitochondria, which are incapable of de novo thymidine synthesis.