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Human Molecular Genetics Advance Access originally published online on July 25, 2007
Human Molecular Genetics 2007 16(20):2472-2481; doi:10.1093/hmg/ddm203
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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{dagger}

George M.C. Janssen1,*,{ddagger}, Paul J. Hensbergen2,{ddagger}, Frans J. van Bussel1, Crina I.A. Balog2, J. Antonie Maassen1, André M. Deelder2 and Anton K. Raap1

1 Department of Molecular Cell Biology and 2 Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Centre, Post Zone S1-P, Einthovenweg 20, PO Box 9600, 2300RC Leiden, The Netherlands

* To whom correspondence should be addressed. Tel: +31 71 526 9263; Fax: +31 71 526 8270; E-mail: G.M.C.Janssen{at}lumc.nl

Received April 26, 2007; Revised June 1, 2007; Accepted July 22, 2007

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.

{dagger} This paper is dedicated to the memory of the late Professor Wim Möller (1930–2005), a remarkable man, molecular biologist at Leiden University and pioneer of ribosome structure and function.

{ddagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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