A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies

Rani, Deepa Selvi; Nallari, Pratibha; Rani, Jhansi; Nizamuddin, Sheikh; Seelamneni, Thulasamma; Narasimhan, Calambur; Thangaraj, Kumarasamy

doi:10.1159/000495027

Cited by 4 publications

(4 citation statements)

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“…Our present comprehensive genetic analysis of the MYBPC3 gene in Indian HCM and DCM patients has given important insight into risk stratification. Based on our present and previous studies on sarcomere genes in Indian population, 23,24,34,35,45,[62][63][64][65][66][67] we fully agree that the mutations in myosin heavy chain and myosin binding protein C are the frequent causes of cardiomyopathies; therefore, these two genes should be screened first, secondly, the thin filament regulatory genes (TNNT2, TNNI3, and TPM1), and finally, the rarely involved genes like TTN, MYL2, MYL3, and ACTC. Importantly, it is not sufficient and advisable to screen only the known reported mutations, because we could miss unique, rare, and population-specific disease-causing mutations.…”

Section: Discussionsupporting

confidence: 76%

“…In our previous studies, we reported a few genetic variations in other sarcomere genes of Indian cardiomyopathy patients: Tropomyosin (α-TMP1), 45 Troponin I3 (TNNI3), 24,62 Troponin T2 (TNNT2), 34,63 Actin (ACTC), 64 Myosin (β-MYH7), 35,65,66 and MYL2 & MYL3. 67 Therefore, our present and previous studies clearly illustrated the prevalence and spectrum of variations in sarcomere genes and their associations in Indian populationwith cardiomyopathies. 23,24,34,35,45,[62][63][64][65][66][67] Our categorization as pathogenic variations relied on the result that we could detect those missense mutations exclusively in patients and their family members.…”

Section: Discussionsupporting

confidence: 72%

“…67 Therefore, our present and previous studies clearly illustrated the prevalence and spectrum of variations in sarcomere genes and their associations in Indian populationwith cardiomyopathies. 23,24,34,35,45,[62][63][64][65][66][67] Our categorization as pathogenic variations relied on the result that we could detect those missense mutations exclusively in patients and their family members. In the present study, we found 19 novel SNPs in the MYBPC3 gene, along with accumulated compound variations that were responsible for more severe disease phenotypes in Indian cardiomyopathies.…”

Section: Discussionsupporting

confidence: 72%

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Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies

Rani,

Kasala,

Dhandapany

et al. 2023

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Background Mutations in Myosin Binding Protein C ( MYBPC3 ) are one of the most frequent causes of cardiomyopathies in the world, but not much data are available in India. Methods We carried out targeted direct sequencing of MYBPC3 in 115 hypertrophic (HCM) and 127 dilated (DCM) cardiomyopathies against 197 ethnically matched healthy controls from India. Results We detected 34 single nucleotide variations in MYBPC3 , of which 19 were novel. We found a splice site mutation [(IVS6+2T) T>G] and 16 missense mutations in Indian cardiomyopathies [5 in HCM; E258K, T262S, H287L, R408M, V483A: 4 in DCM; T146N, V321L, A392T, E393K and 7 in both HCM and DCM; L104M, V158M, S236G, R272C, T290A, G522E, A626V], but those were absent in 197 normal healthy controls. Interestingly, we found 7 out of 16 missense mutations (V158M, E258K, R272C, A392T, V483A, G522E, and A626V) in MYBPC3 were altering the evolutionarily conserved native amino acids, accounted for 8.7% and 6.3% in HCM and DCM, respectively. The bioinformatic tools predicted that those 7 missense mutations were pathogenic. Moreover, the co-segregation of those 7 mutations in families further confirmed their pathogenicity. Remarkably, we also identified compound mutations within the MYBPC3 gene of 6 cardiomyopathy patients (5%) with more severe disease phenotype; of which, 3 were HCM (2.6%) [(1. K244K + E258K + (IVS6+2T) T>G); (2. L104M + G522E + A626V); (3. P186P + G522E + A626V]; and 3 were DCM (2.4%) [(1. 5’UTR + A392T; 2. V158M+G522E; and 3.V158M + T262T + A626V]. Conclusion The present comprehensive study on MYBPC3 has revealed both single and compound mutations in MYBPC3 and their association with disease in Indian Population with Cardiomyopathies. Our findings may perhaps help in initiating diagnostic strategies and eventually recognizing the targets for therapeutic interventions.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 72%

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Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies

Rani,

Kasala,

Dhandapany

et al. 2023

PGPM

Self Cite

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“…Apart from missense mutations, we identified a total of 16 silent or synonymous mutations (4 in both HCM and DCM, 4 in DCM, and remaining 8 are found to be polymorphic) (►Table 2), 2 intronic variations are being detected exclusively in cases. Further, this study data are compared with our previous datasets of seven other sarcomere genes, MYL3, TPM1, ACTC, TNNI3, TNNT2, MYBPC3, and MYL2, 8,14,35,[39][40][41][42] and found no additional causative mutation suggesting nonexistence of compound heterozygosity.…”

Section: Resultsmentioning

confidence: 95%

Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies

et al. 2019

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Background Mutations in β-MYH7 gene is a main genetic cause of cardiomyopathy and sudden cardiac arrest, yet the molecular mechanisms have not been fully understood. Objectives To identify variations in β-MYH7 gene and their possible mechanistic role in cardiomyopathies among Indian women. Methods We sequenced all exons and their flanking regions of the β-MYH7 gene in 188 Indian women consisting of 33 hypertrophic cardiomyopathy (HCM), 48 dilated cardiomyopathy (DCM), and 107 healthy controls. Results Our study showed 21 variations in β-MYH7 gene, including 7 novel mutations. In addition, we compared this dataset with our previously studied datasets of seven other sarcomere genes (ACTC, TNNT2, MYL2, MYBPC3, TPM1, TNNI3, and MYL3) and found no causative mutation, confirming the nonexistence of compound heterozygosity. Interestingly, we detected a Val431Met mutation exclusively in patients, and its pathogenicity has been predicted using the protein homology model. In native, Val431 is evolutionarily conserved across many species. In the homology model, mutant Met431 gets further buried in the hydrophobic core by creating an aberrant hydrophobic interaction with Leu352. As a result, it probably reduces the spatial distances between other hydrophobic interactions in the hydrophobic core that may produce steric hindrance and strain. It may lead to deviation in the structure (root means square deviation [RMSD] of ~3.9), and might possibly causing the cardiac remodeling and cardiomyopathy. Conclusion We identified a novel Val431Met mutation, exclusively in patients, and its homology model p.Met431 has profoundly increased the mechanistic understanding of disease specifically in personalized medicine, to block/inverse/diminish the disease phenotype. AbstractKeywords ► β-MYH7 gene ► homology model ► hypertrophic cardiomyopathy ► dilated cardiomyopathy ► cardiomyopathy

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Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

et al. 2022

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Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.

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A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies

Cited by 4 publications

References 27 publications

Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies

Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies

Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

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