Title: Novel missense mutations in the Head Motor Domain of β-MYH7 gene in Indian cardiomyopathies

Abstract

Background: Heart failure is a hallmark of severe hypertrophic (HCM) and dilated (DCM) cardiomyopathies. Several mutations in the β-MYH7 gene lead to HCM. Recently, causative mutations in the β-MYH7 gene have also been detected in DCM from different populations. Methods: We sequenced the β-MYH7 gene in 137 Indian DCM patients and 167 ethnically matched healthy controls to detect the frequency of mutations and their association. Results: Our study revealed 27 variations, of which seven mutations (8.0%) were detected exclusively in Indian DCM patients for the first time. These included four missense mutations: Arg723His, Phe510Leu, His358Leu, and Ser384Tyr (2.9%), a frameshift mutation: Asn676_Tdel (1.5%), and two splice-site mutations (IVS17+2T) T>G & (IVS19- 1G) G>A (3.6%). Remarkably, all four missense mutations altered evolutionarily conserved amino acids. All four missense mutations were predicted pathogenic by Polymorphism phenotyping v2 (Polyphen-2) and Sorting Intolerant From Tolerant (SIFT), two bioinformatics tools. In addition, the four p. Leu358, p.Tyr384, p.Leu510, and p.His723 homology models of β-MYH7 displayed root-mean-square deviation (RMSD) of ~2.55A0, ~1.24A0, ~3.36A0, and ~3.86A0, respectively. Conclusion: In the present study, we detected numerous novel, unique, and rare mutations in the β-MYH7 gene exclusively in Indian DCM patients (8.0%). Here, we demonstrate how each mutant (missense) uniquely disrupts a critical network of non-bonding interactions at the mutation site (molecular level) and may contribute to dilated cardiomyopathy (DCM). Therefore, our findings may provide insight to understand the molecular bases of disease, diagnosis and promote novel therapeutic strategies (personalized medicine). genes” “HCM”, “DCM”. SNP--single nucleotide polymorphism, SS#.No-- Submitted SNP number, rs#.No--Reference SNP number, PolyPhen-2--Pheno-typing v2,SIFT-- Sorting Intolerant from Tolerant, CON--controls, DCM--Dilated cardiomyopathy,Missense mutations; 4/137= 2.9%; Splice site mutations: 5/137= 3.6%; Frame shift mutations: 2/137= 1.5%; Total mutations in DCM=8.0%.

Biography

Dr. Deepa Selvi Rani is from CCMB-CSIR, India. She is interested in understanding the Genetic basis of Cardiovascular Diseases, Male infertility, Mitochondrial disorders, and the Origin of Modern Humans. She has two master's degrees, M.Sc. in Biochemistry and M.Sc. in Biotechnology. Her Ph.D. work was on "Molecular Studies in Cardiomyopathies and Noonan Syndrome." She identified several mutations in sarcomere protein genes causing cardiomyopathies and sudden cardiac arrest. To understand the disease specifically, she studied their molecular mechanisms, which are relevant to pharmacogenomic studies and personalized medicine. Dr. Rani is an enthusiastic, dedicated, outstanding researcher and published 50 papers in peer-reviewed International Journals. She has a 22 h-index with a total of 1602 citations. https://scholar.google.co.in/citations?hl=en&user=qUgZf-kAAAAJ&view_op=list_works&sortby=pubdate. WIN CARS has recently awarded her "Servier Women Researchers Award" in 2019.