Abstract 4372358: The His651Arg Mutation in <i>β-Myosin</i> gene Causes Dilated Cardiomyopathy (DCM)

Abstract

Background: Inherited dilated cardiomyopathy (DCM) is a structural heart disease characterized by pathological enlargement of the heart. DCM can be caused by a mutation in the β-MYH7 gene that reduces contractile function and leads to heart failure. Methods: This is a case-control study to assess the role of β-MYH7 variations in Indian DCM patients and to differentiate a causative nsSNP and its impact on protein structure. We used targeted direct sequencing of the β-MYH7 gene in 122 DCM patients versus 173 ethnically matched healthy controls. To better define the mechanistic basis of the disease, we studied the structural impact of the mutant protein homology model compared to the native protein. Results: In the present study, we identified a missense mutation (His651Arg) in the head motor domain of β-MYH7 in a DCM patient, which was absent in 173 ethnically matched healthy individuals. The mutant Arginine651 was co-segregated with the disease in the family pedigree. Arg651 was found to alter an evolutionarily conserved amino acid, Histidine651. In addition, the mutant R651 was predicted to be pathogenic by the PolyPhen-2 and SIFT bioinformatics tools. Additionally, the superimposed 3D structure of the mutant (p.Arg651 homology model) compared to the native (p.His651) exhibited a root mean square deviation (RMSD) of approximately 3.6 Å. It is well known that non-covalent interactions—such as hydrophobic, electrostatic, Van der Waals, and hydrogen bonds—are crucial for stabilizing protein structures. Our findings demonstrated how the mutant (p.Arg651) disrupts a critical network of non-covalent interactions at the mutation site, potentially contributing to the disease phenotype. Conclusion: We identified a Novel H651R Mutation in the β-MYH7 Gene that led to DCM in India. Hence, our findings may pave the way for the development of small molecular modulators or myosin-targeted therapies for heart failure in the future.