Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot?

TLDR

We identified two patients carrying pathogenic single‑nucleotide mutations in distinct mitochondrial tRNA genes—one in tRNA(Asn) and another in tRNA(Leu(UUR)). The tRNA(Asn) mutation caused isolated ophthalmoplegia, whereas the tRNA(Leu(UUR)) mutation produced a MERRF‑like neurological syndrome with optic neuropathy, retinopathy, and diabetes; both mutations were heteroplasmic, with pathogenic effects manifesting only when mutant mtDNA exceeded 90%, and the frequent occurrence of tRNA(Leu(UUR)) mutations indicates this gene is an etiologic hot spot.

Abstract

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.