Novel Single Residue Mutation in the B-MYH7 gene and their impact in Cardiomyopathies

2^nd World Congress on Heart

April 25-26, 2022 | Webinar

Deepa Selvi Rani

CSIR-Centre for Cellular and Molecular Biology, India

Scientific Tracks Abstracts: J Cardiovasc Dis Diagn

Abstract :

Heart failure is a hallmark of severe hypertrophic (HCM) and dilated (DCM) cardiomyopathies. Mutations in the B-MYH7 gene are the known cause for cardiomyopathies (CM), yet the mechanism has not been fully understood. Methods: We sequenced the B-MYH7 gene in 101 HCM and 147 DCM patients along with 207 ethnically matched healthy controls to detect the frequency of mutations and their association. Results: Our study revealed 45 variations, of which 29 were novel including 3 splice-sites variations; [(IVS17+2T) T>G, (IVS7-1G) G>A, (IVS19- 1G) G>A], and 3 frame-shifts mutations; [Asn602 (A-ins), Asn676 (T-del), Gln789 (A-del)]. Interestingly, we observed 9 missense mutations; [p.His358Leu, p.Met362Leu, p.Ser384Tyr, p.Ala423Thr, p.Val431Met, p.Phe510Leu, p.Glu525Lys, p.Arg723His, p.Asp896Asn]. Except p.Ala423Thr remaining 7 missense mutations in the head motor domain of B-MYH7 were evolutionarily conserved across many species. These 7 mutants were predicted pathogenic by Polymorphism phenotyping v2 (Polyphen-2) and Sorting Intolerant From Tolerant (SIFT), bioinformatics tools. In addition, these mutants; p.His358Leu, p.Met362Leu, p.Ser384Tyr, p.Ala423Thr, p.Val431Met, p.Phe510Leu, p.Glu525Lys, p.Arg723His, displayed root-mean-square deviation (RMSD) of ~2.55A0, ~1.85A0, ~1.24A0, ~1.17A0, ~3.90A0, ~3.36A0, ~0.77A0, and ~3.86A0, respectively. Conclusion: In the present study, we detected numerous novel, unique, and rare mutations in the B-MYH7 gene exclusively in Indian cardiomyopathy patients. 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 cardiomyopathy (CM). Therefore, our findings may provide insight to understand the molecular bases of disease, diagnosis and promote novel therapeutic strategies (personalized medicine). Keywords: “B-MYH7”, “Cardiomyopathy”, “homology models”, “3D structure”, “Sarcomere genes” “HCM”, “DCM”. Recent Publications: Deepa Selvi Rani, Kumar AV, Nallari P, Sampathkumar K, Dhandapany PS, Narasimhan C, Rathinavel A, Thangaraj K. (2021). Novel mutations in B-MYH7 gene in Indian patients with dilated cardiomyopathy, CJC Open. DOI: 10.1055/s-0039-1694829. Deepa Selvi Rani, Rajender S, Pavani K, Chaubey G, Rasalkar AA, Gupta NJ, Deendayal M, Chakravarty B, Thangaraj K. (2019). “High frequencies of Non-Allelic Homologous Recombination (NAHR) events at the AZF loci and male infertility risk in Indian men”. Sci Rep. 18; 9(1): 6276. doi: 10.1038/s41598-019-42690. Deepa Selvi Rani, PS Dhandapany, P Nallari, J Rani, K Meraj, G. Mala, C Narasimhan, K Thangaraj (2015). “Co-existence of digenic mutations in both thin (TPM1) and thick (MYH7) filaments of sarcomeric genes lead to severe hypertrophic cardiomyopathy in a south Indian FHCM". DNA and Cell Biology; 34 (5),350-359. Dhandapany PS, Razzaque MA, Muthusami U, Kunnoth S, Edwards JJ, Mulero-Navarro S, Riess I, Pardo S, Sheng J, Deepa Selvi Rani, Rani B, Govindaraj P, Flex E, Yokota T, Furutani M, Nishizawa T, Nakanishi T, Robbins J, Limongelli G, Hajjar RJ, Lebeche D, Bahl A, Khullar M, Rathinavel A, Sadler KC, Tartaglia M, Matsuoka R, Thangaraj K, Gelb BD (2014). “RAF1 mutations in childhoodonset dilated cardiomyopathy”. Nature genetics. 46 (6): 635-639. doi:10.1038/ng.2963.Deepa Selvi Rani, PS Dhandapany, P Nallari, C Narasimhan, K Thangaraj (2014). A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM). PloS one 9 (7), e101451. Deepa Selvi Rani, Nallari P, Priyamvada S, Narasimhan C, Singh L, Thangaraj K (2012). “High prevalence of Arginine to Glutamine substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians”. BMC medical genetics; 13:69. doi:10.1186/1471-2350-13-69. Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Deepa Selvi Rani, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards MB, Price AL, Patterson N, Reich D, Singh L, Tyler-Smith C, Thangaraj K. (2009). “A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia”. Nature genetics. 41(2): 187-91. doi: 10.1038/ng.309.

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://sc holar.google.co.in/citations?hl=en&user=qUgZfkAAAAJ& view_op=list_works&sortby=pubdate. WIN CARS has recently awarded her "Servier Women Researchers Award" in 2019