Human Molecular Genetics Advance Access originally published online on September 9, 2005
Human Molecular Genetics 2005 14(20):3079-3088; doi:10.1093/hmg/ddi341
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Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy
1Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy, 2CNR Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy, 3Division of Molecular Neurogenetics, National Neurological Institute ‘Carlo Besta’, 20126 Milano, Italy, 4Department of Genetics Anthropology Evolution, University of Parma, 43100 Parma, Italy and 5Department of Neurology and 6Department of Anatomy, University Medical Centre, Ljubljana, Slovenia
* To whom correspondence should be addressed at: Divisione di Neurogenetica Molecolare, Istituto Nazionale Neurologico Carlo Besta, Via Temolo 4, 20126 Milano, Italy. Tel: +39 0223942630; Fax: +39 022394619; Email: zeviani{at}istituto-besta.it
Received July 15, 2005; Revised August 30, 2005; Accepted September 7, 2005
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 progressive external opthalmoplegia 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 knockout 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 Oxidative Phosphorylation phenotype displayed by WB-12, an AAC1/AAC2 defective strain. Interestingly, exposure to reactive oxygen species (ROS) 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.
Present address: Department of Neurology, University of Miami School of Medicine, Miami, FL, USA.
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