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Mitochondrial DNA mutations in cardiomyopathy
1Department of Internal Medicine II, Faculty of Medicine, University of Nagoya, Japan.
Insights
Mitochondrial DNA (mtDNA) deletions are common in dilated cardiomyopathy, while point mutations in tRNA genes are linked to hypertrophic cardiomyopathy and MELAS syndrome, indicating mtDNA
Area of Science:
- Cardiology
- Genetics
- Mitochondrial Biology
Background:
- Cardiomyopathies, including dilated and hypertrophic types, can have genetic underpinnings.
- Mitochondrial DNA (mtDNA) mutations are implicated in various human diseases.
Purpose of the Study:
- To investigate deletions and point mutations in mitochondrial DNA (mtDNA) of patients with dilated or hypertrophic cardiomyopathy.
- To identify specific mtDNA alterations associated with different cardiomyopathy phenotypes and related syndromes.
Main Methods:
- Polymerase chain reaction (PCR) and fluorescence-based direct sequencing were employed to analyze mtDNA.
- Sequencing identified deletions, direct repeats, and point mutations in specific genes.
Main Results:
- Frequent mtDNA deletions were observed in patients with dilated cardiomyopathy, often flanked by direct repeats in the ATPase6 gene and D-loop region.
- A patient with hypertrophic cardiomyopathy and left ventricular dilatation exhibited a large mtDNA deletion (7,079 bp) and unique point mutations in tRNA(Cys) and tRNA(Thr) genes.
- A patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) presented with an A-to-G transition in the tRNA(Leu)(UUR) gene.
Conclusions:
- mtDNA deletions are prevalent in dilated cardiomyopathy.
- Specific point mutations in mtDNA tRNA genes are associated with hypertrophic cardiomyopathy and MELAS.
- mtDNA mutations should be suspected in patients with hypertrophic cardiomyopathy and lactic acidosis.
Abstract:
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 tRNA(Cys) gene (nucleotide position 5,821) at the aminoacyl acceptor stem and an A-to-G transition in the tRNA(Thr) gene (nucleotide position 15,951) were identified. In a patient with MELAS, an A-to-G transition in the tRNA(Leu)(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.(ABSTRACT TRUNCATED AT 250 WORDS)