Point mutations in mitochondrial DNA of patients with dilated cardiomyopathy.

Mitochondrial (mt) DNA mutations are hypothesized to be involved in the pathogenesis of dilated cardiomyopathy, because the mtDNA encodes 13 polypeptides that are essential for oxidative phosphorylation, upon which the heart relies for energy. To test this hypothesis, we amplified the mitochondrial genome by long PCR and then used restriction analysis and direct sequencing to examine 58 unrelated patients with dilated cardiomyopathy and 49 controls for the detection of point mutations. The results demonstrated that point mutations were significantly more frequent in the mtDNA of patients than in that of controls (173 in 58 patients v 54 in 49 controls, 2=16.51, P<0.001). In addition to normal variants and mutations common to both patients and controls, 43 mutations were identified only in patients. All but four of these mutations were homoplasmic. Mutations involving the evolutionarily conserved residues of cytochrome c oxidase subunit I, NADH dehydrogenase 5, tRNAAla and tRNAArg were identified. As many as 13 point mutations were found in an 8-month-old patient. In conclusion, there exist significantly more point mutations in mtDNA of patients than in controls, suggesting that multiple mutations may exert a cumulative effect on heart function. Thus, by altering the function of respiratory enzyme subunits or tRNAs, mtDNA point mutations could be relevant for the pathogenesis of dilated cardiomyopathy.