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Mitochondrial DNA mutations in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
1Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
Abstract:
The total sequences of mitochondrial DNA were determined in two patients with juvenile-onset mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to Complex I deficiency. Patients 1 and 2 had three and two unique point mutations, respectively, causing replacement of phylogenically conserved amino acids. A transition from G to A was found at nucleotide position 5601 in the alanine tRNA gene of Patient 2, and a transition from A to G was found at 3243 in the leucine (UUR) tRNA gene of both patients. The latter mutation located at the phylogenically conserved 5' end of the dihydrouridine loop of the tRNA molecule, and was present in two patients with adult-onset MELAS and absent in controls. These results indicate that a mass of mtDNA mutations including the A-to-G transition in the tRNA(Leu) gene is a genetic cause of MELAS.
Insights
Mitochondrial DNA mutations, including a specific A-to-G change in the tRNA(Leu) gene, are identified as a cause of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This finding sheds light on the genetic basis of this severe neurological disorder.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a severe maternally inherited disorder.
- Complex I deficiency is a common cause of MELAS, often linked to mitochondrial DNA (mtDNA) mutations.
Observation:
- Two patients with juvenile-onset MELAS and Complex I deficiency underwent total mitochondrial DNA sequencing.
- Multiple unique point mutations were identified in both patients, affecting phylogenically conserved amino acids.
Findings:
- A novel G-to-A transition at nucleotide 5601 in the alanine tRNA gene was found in Patient 2.
- A significant A-to-G transition at nucleotide 3243 in the leucine (UUR) tRNA gene was identified in both patients.
- This A-to-G mutation at position 3243, located in a conserved region of the tRNA molecule, was also present in adult-onset MELAS patients and absent in controls.
Implications:
- The study indicates that a combination of mtDNA mutations, particularly the A-to-G transition in the tRNA(Leu) gene, is a genetic cause of MELAS.
- These findings contribute to understanding the molecular mechanisms underlying MELAS.
- Identifying specific mtDNA mutations can aid in diagnosis and potentially inform future therapeutic strategies for MELAS.