Studies on the Mitochondrial tRNA Gene Variants in Patients with Coronary Artery Disease and Pathogenicity Assessment by in silico Analysis
Studies on the Mitochondrial tRNA Gene Variants in Patients with Coronary Artery Disease and Pathogenicity Assessment by in silico Analysis
Fayaz Khan1, Aziz Uddin1, Hisham N. Altayb2, Bibi Nazia Murtaza3,
Sajid Ul Ghafoor1, Faisal Imam4, Saima Iftikhar5, Sadia Tabassum1,
Khushi Muhammad1* and Muhammad Shahid Nadeem2
ABSTRACT
Mutations in mitochondrial DNA (mtDNA) have been associated with many pathological conditions including cardiovascular diseases. In the present study, we have evaluated the mutations in the mitochondrial tRNA genes for leucine, threonine and proline in patients with coronary artery disease (CAD). It included a large family with 11 cases and 29 healthy individuals. Mitochondrial tRNA genes were PCR amplified and analyzed for nucleotide sequences. Mutations were identified and the variants of genes were evaluated for structural variations by in silico analysis. Pathogenicity of individual tRNA variants was determined by molecular docking analysis and application of scoring systems such as MSeqDR, MitoTIP, HMTVar and PON-mt-tRNA. Four tRNA gene mutations including tRNALeu (m.12285T>C, m.12308A>G), tRNAThr (m.15928G>A), and tRNAPro (m.15968T>C) were identified, m.12285 T>C and m.15968T>C being novel to CAD. Score based pathogenicity analysis of tRNA variants with MSeqDR, MitoTIP, HMTVar and PON-mt-tRNA have suggested that the variants were either likely or possibly polymorphic. Molecular docking studies of variants have shown significant difference in their structure, binding position and binding affinities with corresponding amino acyl tRNA synthetase. In silico results with structural abnormalities and molecular docking studies reflecting a failure of tRNA variants to bind the corresponding enzymes designate the potential role of identified variants in CAD pathogenicity. We have identified CAD specific variants in tRNA genes. These studies provide tRNA variants that can be applied for the early detection and screening of young populations for CAD.
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