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.
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.
Authors: M Zeviani; C Gellera; C Antozzi; M Rimoldi; L Morandi; F Villani; V Tiranti; S DiDonato Journal: Lancet Date: 1991-07-20 Impact factor: 79.321