Mitochondrial DNA Mutations in Cardiomyopathy : MOLECULAR ANALYSIS OF THE PATHOPHYSIOLOGY OF CARDIOMYPATHY

Deletions and point mutations of mitochondrial DNA (mtDNA) of patients with dilated or hypertrophic cardiomyopathy were analyzed using the polymerase chain reaction and fluorescence-based direct sequencing. The patients included are with hypertrophic cardiomyopathy associated with left ventricular dilatation, a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and a patient with fatal infantile cardiomyopathy. Deletions were frequently seen in mtDNA in patients with dilated cardiomyopathy. The mtDNA was sequenced and the direct repeat at each edge of deletion was identified as (5'-CATCAACAACCG-3') which was located in the ATPase6 gene and in the D-loop region. In a patient with hypertrophic cardiomyopathy associated with left ventricular dilatation, another mutant mtDNA was found not to have directly repeated sequence, and was revealed to jump from nucleotide position 8, 992 to position 16, 072 of mtDNA resulting in a 7, 079 bp deletion. This patient had unique point mutation in the tRNA genes. A G-to-A transition in the tRNACys gene (nucleotide position 5, 821) at the aminoacyl acceptor stem and an A-to-G transition in the tRNAThr gene (nucleotide position 15, 951) were identified. In a patient with MELAS, an A-to-G transition in the tRNALeu(UUR) gene (nucleotide position 3, 243) was observed. This mutation was located at the 5' end of the dihydrouridine loop of this tRNA molecule, and would disturb its function. In a patient with hypertrophic cardiomyopathy associated with lactic acidosis, mutations of mtDNA should be suspected. In a patient with fatal infantile cardiomyopathy, three point mutations in the genes of tRNALeu (nucleotide position 3, 254), tRNAIle (nucleotide position 4, 317), and tRNATrp (nucleotide position 5, 554) were identified. From these data, it is suggested that mtDNA deletions and point mutations which induce base substitutions in protein subunit genes, and base substitutions in tRNA genes which affect the function of the mitochondrial respiratory chain are important contributory factors to the genesis of some forms of cardiomyopathy.