Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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S Zarrouk-Mahjoub1, S Mehri, F Ouarda
1Laboratory of Biochemistry, UR "Human Nutrition and Metabolic Disorders" Faculty of Medicine, Monastir University, Monastir, Tunisia.
Insights
A novel mitochondrial DNA variant, m.4395A>G, was identified in a patient with hypertrophic cardiomyopathy (hCMP). This variant may negatively impact heart function, contributing to hCMP development.
Area of Science:
- Cardiology
- Genetics
- Mitochondrial Biology
Background:
- Mitochondria are crucial for cardiac myocyte survival and death.
- Mitochondrial DNA (mtDNA) mutations can lead to mitochondrial dysfunction and cardiomyopathies (CMPs).
- Investigating the specific mitochondrial defect in hypertrophic cardiomyopathy (hCMP) is essential for understanding disease mechanisms.
Observation:
- A 14-year-old male patient with hCMP, preexcitation syndrome, and ventricular arrhythmias was analyzed.
- DNA sequencing identified four mtDNA variants, including a novel m.4395A>G transition in the MT-TQ gene.
- The m.4395A>G variant affects a highly conserved nucleotide and a U.G base pair in MT-TQ secondary structure.
Findings:
- The m.4395A>G variant alters an evolutionarily conserved nucleotide.
- Computational analyses predict the m.4395A>G variant as possibly pathogenic.
- Additional known polymorphisms in the MT-CYB gene were also detected.
Implications:
- The identified m.4395A>G variant is a potential contributor to hCMP.
- Understanding this mitochondrial defect could lead to improved diagnostics and therapeutics for cardiomyopathies.
- Further research is warranted to elucidate the precise role of this variant in cardiac dysfunction.
Background:
Mitochondria play critical roles in both the life and death of cardiac myocytes. Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathies (CMPs). Our aim was to investigate the underlying mitochondrial defect in a patient with hypertrophic cardiomyopathy (hCMP). A detailed clinical and molecular genetic analysis was performed.
Patients And Methods:
Total DNA was extracted from lymphocytes in a 14-year-old index male patient with hCMP, preexcitation syndrome, and severe ventricular arrhythmias. Direct sequencing of the PCR fragments was performed. To distinguish deleterious from functionally neutral variants, the ClustalW program, RNAfold software, and PolyPhen algorithm were applied, which predict the pathogenicity of a particular variant by using a set of empirical rules based on the nature of the mutation, the phylogenetic conservation of the variant, and the physicochemical property of the amino acid.
Results:
The mutational analysis of mtDNA genes revealed four variants. The m.4395A>G transition (C6G) in the MT-TQ gene, which altered an evolutionary conserved nucleotide, with a conservation index of 85.7 % and affected a highly conserved U.G base pair in the secondary structure of MT-TQ. Additionally, the previously reported polymorphisms m.14757T>A, m.15236A>G, and m.15314G>A resulting in the replacement of amino acid residues in the MT-CYB gene were detected.
Conclusion:
The m.4395A>G variant was scored as possibly pathogenic and may exert a negative effect on heart function to generate hCMP.
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