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Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies

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 aga...

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Autores principales: Rani, Deepa Selvi, Kasala, Apoorva, Dhandapany, Perundurai S, Muthusami, Uthiralingam, Kunnoth, Sreejith, Rathinavel, Andiappan, Ayapati, Dharma Rakshak, Thangaraj, Kumarasamy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518145/
https://www.ncbi.nlm.nih.gov/pubmed/37750083
http://dx.doi.org/10.2147/PGPM.S407179
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author Rani, Deepa Selvi
Kasala, Apoorva
Dhandapany, Perundurai S
Muthusami, Uthiralingam
Kunnoth, Sreejith
Rathinavel, Andiappan
Ayapati, Dharma Rakshak
Thangaraj, Kumarasamy
author_facet Rani, Deepa Selvi
Kasala, Apoorva
Dhandapany, Perundurai S
Muthusami, Uthiralingam
Kunnoth, Sreejith
Rathinavel, Andiappan
Ayapati, Dharma Rakshak
Thangaraj, Kumarasamy
author_sort Rani, Deepa Selvi
collection PubMed
description 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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spelling pubmed-105181452023-09-25 Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies Rani, Deepa Selvi Kasala, Apoorva Dhandapany, Perundurai S Muthusami, Uthiralingam Kunnoth, Sreejith Rathinavel, Andiappan Ayapati, Dharma Rakshak Thangaraj, Kumarasamy Pharmgenomics Pers Med Original Research 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. Dove 2023-09-20 /pmc/articles/PMC10518145/ /pubmed/37750083 http://dx.doi.org/10.2147/PGPM.S407179 Text en © 2023 Rani et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Rani, Deepa Selvi
Kasala, Apoorva
Dhandapany, Perundurai S
Muthusami, Uthiralingam
Kunnoth, Sreejith
Rathinavel, Andiappan
Ayapati, Dharma Rakshak
Thangaraj, Kumarasamy
Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title_full Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title_fullStr Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title_full_unstemmed Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title_short Novel MYBPC3 Mutations in Indian Population with Cardiomyopathies
title_sort novel mybpc3 mutations in indian population with cardiomyopathies
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518145/
https://www.ncbi.nlm.nih.gov/pubmed/37750083
http://dx.doi.org/10.2147/PGPM.S407179
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