Two Novel Pathogenic Mitochondrial DNA Mutations Affecting Organelle Number and Protein Synthesis: Is the tRNALeu(UUR) Gene an Etiologic Hot Spot?

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Abstract

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes:the first mutation in the tRNAAsn gene, and the ninth known mutation in the tRNALeu(UUR) gene. The mutation in tRNAAsn was associated with isolated ophthalmoplegia, whereas the mutation in tRNALeu(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 tRNALeu(UUR) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease. (J. Clin. Invest. 1993. 92:2906-2915.) Key words: mitochondrial DNA. mitochondrial disorders. tRNA identity. diabetes. ophthalmoparesis

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