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Human Molecular Genetics Advance Access published online on September 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi341
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received July 15, 2005
Revised August 30, 2005
Accepted September 7, 2005

Article

Complete loss of function of the heart/muscle specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy

Luigi Palmieri 1, Simona Alberio 2, Isabella Pisano 3, Tiziana Lodi 4, Mija Meznaric-Petrusa 5, Janez Zidar 5, Antonella Santoro 1, Pasquale Scarcia 3, Flavia Fontanesi 4, Eleonora Lamantea 2, Iliana Ferrero 4, and Massimo Zeviani 6*

1 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy; CNR Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy
2 Division of Molecular Neurogenetics, National Neurological Institute "C. Besta", 20126 Milano, Italy
3 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy
4 Department of Genetics Anthropology Evolution, University of Parma, 43100 Parma, Italy
5 Department of Neurology, University Medical Centre, Ljubljana, Slovenia
6 Divisione di Neurogenetica Molecolare, Istituto Nazionale Neurologico Carlo Besta, Via Temolo 4, 20126 Milano, Italy

* To whom correspondence should be addressed.
Massimo Zeviani, E-mail: zeviani{at}istituto-besta.it


  Abstract

Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant PEO and in a sporadic patient. We herein report on a sporadic patient who presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance and lactic acidosis, but no ophthalmoplegia. A muscle biopsy showed the presence of numerous ragged red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Molecular analysis revealed a C to A homozygous mutation at nucleotide 368 of the ANT1 gene. The mutation converted a highly conserved alanine into an aspartic acid at codon 123 and was absent in 500 control individuals. This is the first report of a recessive mutation in the ANT1 gene. The clinical and biochemical features are different from those found in dominant ANT1 mutations, resembling those described in ANT1 KO mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe OXPHOS phenotype displayed by WB-12, an AAC1/AAC2 defective strain. Interestingly, exposure to reactive oxygen species scavengers dramatically increased the viability of the WB-12 transformant, suggesting that increased redox stress is involved in the pathogenesis of the disease and that anti-ROS therapy may be beneficial to patients.


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