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Human Molecular Genetics, 2000, Vol. 9, No. 4 467-475
© 2000 Oxford University Press

Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients

G. Valentin Börner1,2,+, Massimo Zeviani3, Valeria Tiranti3, Franco Carrara3, Sabine Hoffmann4, Klaus Dieter Gerbitz4, Hanns Lochmüller5, Dieter Pongratz5, Thomas Klopstock6, Atle Melberg7, Elisabeth Holme8 and Svante Pääbo1

1Max-Planck-Institute for Evolutionary Anthropology, Inselstrasse 22, D-04103 Leipzig, Germany, 2Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA, 3Istituto Nazionale Neurologico ‘Carlo Besta’, Divisione di Biochemica e Genetica, Via Celoria 11, I-20133 Milano, Italy, 4Institutes for Clinical Chemistry and Diabetes Research, Academic Hospital Schwabing, D-80804 Munich, Germany, 5Friedrich Baur Institut, University of Munich, Ziemsenstrasse 1a, D-80336 Munich, Germany, 6Department of Neurology, Klinikum Großhadern, University of Munich, D-82366 Munich, Germany, 7Department of Neuroscience, Neurology, University Hospital, S-751 85 Uppsala, Sweden and 8Department of Clinical Chemistry, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNALeu(UUR) gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNALys gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNALeu, the A8344G mutation does not affect tRNALys function in the same way.

+ To whom correspondence should be addressed. Tel: +1 617 495 4396; Fax: +1 617 495 0758; Email: boerner@fas.harvard.edu


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