The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy

Mitochondrial DNA (mtDNA) mutations have been causally linked with cardiomy opathies, both dilated (DCM) and hypertrophic. We identified the T12297C mu tation in the mtDNA-tRNA(Leu(CUN)) of a 36-year-old male patient diagnosed with DCM. The mutation was heteroplasmic, with high amount (88%) of mutant DNA in the myocardium, and was absent in normal (n=120) and disease (n=150) controls. It affects a highly conserved nucleotide (adjacent to the antico don triplet) that allows the phospho-ribose backbone to turn and form the l oop. The potential pathological role of T12297C mutation is further support ed by its recent identification in another unrelated Italian family with DC M associated with endocardial fibroelastosis. In the variable loop of the s ame tRNA, our patient also carried the A12308G transition that is debated a s pathological mutation or neutral polymorphism in progressive external oph thalmoplegia: the two defects could exert a synergistic effect on the tRNA structure and function. The endomyocardial biopsy study showed abnormal rin g-like mitochondria and occasional cytochrome c oxydase negative myocytes. Overall, the heteroplasmy, the highly conserved position of the mutated nuc leotide, the absence of the mutation in large series of diseased and normal controls, and the cardiac mitochondrial changes support a causative link o f the mutation with the disease.