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

TitlePartial tandem duplication of mtDNA-tRNA(Phe) impairs mtDNA translation in late-onset mitochondrial myopathy.
Publication TypeJournal Article
Year of Publication2012
AuthorsArzuffi, P, Lamperti, C, Fernandez-Vizarra, E, Tonin, P, Morandi, L, Zeviani, M
JournalNeuromuscul Disord
Date Published2012 Jan
KeywordsAged, 80 and over, Biopsy, DNA Mutational Analysis, DNA, Mitochondrial, Electromyography, Electron Transport Complex IV, Female, Humans, Male, Middle Aged, Mitochondria, Mitochondrial Myopathies, Mitochondrial Proteins, Muscle, Skeletal, Protein Biosynthesis, RNA, Transfer, Phe

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.

Alternate JournalNeuromuscul. Disord.
Citation Key10.1016/j.nmd.2011.07.009
PubMed ID22227277
PubMed Central IDPMC3334271
Grant ListGGP07019 / / Telethon / Italy
GPP10005 / / Telethon / Italy