Partial tandem duplication of mtDNA-tRNA(Phe) impairs mtDNA translation in late-onset mitochondrial myopathy.

Paola Arzuffi, Costanza Lamperti, Erika Fernandez-Vizarra, Paola Tonin, Lucia Morandi, Massimo Zeviani

Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology-IRCCS, Milan, Italy.

Neuromuscular disorders : NMD 2012 Jan

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An 80-year-old woman (PI) has been suffering of late onset progressive weakness and wasting of lower-limb muscles, accompanied by high creatine kinase levels in blood. A muscle biopsy, performed at 63 years, showed myopathic features with partial deficiency of cytochrome c oxidase. A second biopsy taken 7 years later confirmed the presence of a mitochondrial myopathy but also of vacuolar degeneration and other morphological features resembling inclusion body myopathy. Her 46-year-old daughter (PII) and 50-year-old son (PIII) are clinically normal, but the creatine kinase levels were moderately elevated and the EMG was consistently myopathic in both. Analysis of mitochondrial DNA sequence revealed in all three patients a novel, homoplasmic 15 bp tandem duplication adjacent to the 5' end of mitochondrial tRNA(Phe) gene, encompassing the first 11 nucleotides of this gene and the four terminal nucleotides of the adjacent D-loop region. Both mutant fibroblasts and cybrids showed low oxygen consumption rate, reduced mitochondrial protein synthesis, and decreased mitochondrial tRNA(Phe) amount. These findings are consistent with an unconventional pathogenic mechanism causing the tandem duplication to interfere with the maturation of the mitochondrial tRNA(Phe) transcript. Copyright © 2011 Elsevier B.V. All rights reserved.

Citation

Paola Arzuffi, Costanza Lamperti, Erika Fernandez-Vizarra, Paola Tonin, Lucia Morandi, Massimo Zeviani. Partial tandem duplication of mtDNA-tRNA(Phe) impairs mtDNA translation in late-onset mitochondrial myopathy. Neuromuscular disorders : NMD. 2012 Jan;22(1):50-5