Avtor/Urednik		Palmieri, Luigi; Alberio, Simona; Pisano, Isabella; Lodi, Tiziana; Meznarič-Petruša, Mija; Zidar, Janez; Santoro, Antonella; Scarcia, Pasquale; Fontanesi, Flavia; Lamantea, Eleonora
Naslov		Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is asoociated with mitochondrial myopathy and cardiomyopathy
Tip		članek
Vir		Hum Mol Genet
Vol. in št.		Letnik 14, št. 20
Leto izdaje		2005
Obseg		str. 3079-88
Jezik		eng
Abstrakt		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 AAC1lAAC2 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.
Deskriptorji		OPHTHALMOPLEGIA, CHRONIC PROGRESSIVE EXTERNAL CARDIOMYOPATHY, HYPERTROPHIC ACIDOSIS, LACTIC DNA, MITOCHONDRIAL ADENINE NUCLEOTIDE TRANSLOCASE BLOTTING, SOUTHERN BLOTTING, WESTERN MUSCLES BIOPSY ADENOSINE TRIPHOSPHATE HOMOZYGOTE CELL SURVIVAL ADULT