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A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients
Abstract:
We identified a novel heteroplasmic mutation in the mitochodrial DNA gene encoding the ND5 subunit of complex I. This mutation (13514A-->G) hits the same codon affected by a previously reported mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)-associated mutation (13513G-->A), but the amino acid replacement is different (D393G vs D393N). The 13514A-->G mutation was found in two unrelated MELAS-like patients. However, in contrast to typical MELAS, lactic acidosis was absent or mild and the muscle biopsy was morphologically normal. Strongly positive correlation between the percentage of heteroplasmy and defective activity of complex I was found in cybrids. We found an additional 13513G-->A-positive case, affected by a progressive mitochondrial encephalomyopathy. Our results clearly demonstrate that the amino acid position D393 is crucial for the function of complex I. Search for D393 mutations should be part of the routine screening for mitochondrial disorders.
Insights
A novel mitochondrial DNA mutation (13514A-->G) in the ND5 gene causes MELAS-like symptoms. This finding highlights the critical role of amino acid position D393 in Complex I function.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Mitochondrial disorders, such as mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), are often caused by mutations in mitochondrial DNA (mtDNA).
- Complex I is a key enzyme in the mitochondrial electron transport chain, and its dysfunction can lead to severe neurological and metabolic diseases.
Observation:
- A novel heteroplasmic mutation (13514A-->G) was identified in the ND5 gene, affecting the same codon as a known MELAS mutation but resulting in a different amino acid change (D393G vs. D393N).
- This mutation was found in two unrelated patients presenting with MELAS-like symptoms, characterized by the absence or mildness of lactic acidosis and normal muscle biopsy findings.
Findings:
- A strong positive correlation was observed between the percentage of heteroplasmy and defective Complex I activity in cybrid cells.
- The study identified an additional patient with a known 13513G-->A mutation exhibiting progressive mitochondrial encephalomyopathy.
- These findings underscore the critical importance of amino acid position D393 for Complex I function.
Implications:
- The identification of the 13514A-->G mutation expands the spectrum of genetic causes for MELAS-like phenotypes.
- Routine screening for mutations at D393 in the ND5 gene should be considered for patients with suspected mitochondrial disorders.
- Understanding the functional impact of specific mtDNA mutations can lead to improved diagnostics and potential therapeutic strategies for mitochondrial diseases.