Journal Article

The A3243G tRNA<sup>Leu(UUR)</sup> mutation induces mitochondrial dysfunction and variable disease expression without dominant negative acting translational defects in complex IV subunits at UUR codons†

George M.C. Janssen, Paul J. Hensbergen, Frans J. van Bussel, Crina I.A. Balog, J. Antonie Maassen, André M. Deelder and Anton K. Raap

in Human Molecular Genetics

Volume 16, issue 20, pages 2472-2481
Published in print October 2007 | ISSN: 0964-6906
Published online July 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm203
The A3243G tRNALeu(UUR) mutation induces mitochondrial dysfunction and variable disease expression without dominant negative acting translational defects in complex IV subunits at UUR codons†

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Mutations in the mitochondrial tRNALeu(UUR) gene are associated with a large variety of human diseases through a largely undisclosed mechanism. The A3243G tRNALeu(UUR) mutation leads to reduction of mitochondrial DNA (mtDNA)-encoded proteins and oxidative phosphorylation activity even when the cells are competent in mitochondrial translation. These two aspects led to the suggestion that a dominant negative factor may underlie the diversity of disease expression. Here we test the hypothesis that A3243G tRNALeu(UUR) generates such a dominant negative gain-of-function defect through misincorporation of amino acids at UUR codons of mtDNA-encoded proteins. Using an anti-complex IV immunocapture technique and mass spectrometry, we show that the mtDNA-encoded cytochrome c oxidase I (COX I) and COX II exist exclusively with the correct amino acid sequences in A3243G cells in a misassembled complex IV. A dominant negative component therefore cannot account for disease phenotype, leaving tissue-specific accumulation by mtDNA segregation as the most likely cause of variable mitochondrial disease expression.

Journal Article.  6360 words.  Illustrated.

Subjects: Genetics and Genomics

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