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A low prevalence of MYH7/MYBPC3 mutations among Familial Hypertrophic Cardiomyopathy patients in India

Abstract

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disorder affecting the cardiac muscle and exhibits varied clinical symptoms because of genetic heterogeneity. Several disease causing genes have been identified and most code for sarcomere proteins. In the current study, we have carried out clinical and molecular analysis of FHC patients from India. FHC was detected using echocardiography and by analysis of clinical symptoms and family history. Disease causing mutations in the β-cardiac myosin heavy chain (MYH7) and Myosin binding protein C3 (MYBPC3) genes were identified using Polymerase Chain Reaction-Deoxyribose Nucleic Acid (PCR-DNA) sequencing. Of the 55 patient samples screened, mutations were detected in only nineteen in the two genes; MYBPC3 mutations were identified in 12 patients while MYH7 mutations were identified in five, two patients exhibited double heterozygosity. All four MYH7 mutations were missense mutations, whereas only 3/9 MYPBC3 mutations were missense mutations. Four novel mutations in MYBPC3 viz. c.456delC, c.2128G>A (p.E710K), c.3641G>A (p.W1214X), and c.3656T>C (p.L1219P) and one in MYH7 viz. c.965C>T (p.S322F) were identified. A majority of missense mutations affected conserved amino acid residues and were predicted to alter the structure of the corresponding mutant proteins. The study has revealed a greater frequency of occurrence of MYBPC3 mutations when compared to MYH7 mutations.

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Acknowledgments

We are thankful to the patients, their family members and the control subjects for their co-operation in this study. We are thankful to Mr. Chelasani Venkat Reddy for help in making Fig. 2a, b. We are also thankful to Mr. A. S. Raju for critical reading of the manuscript. The study was supported by a grant from the Department of Biotechnology, Government of India (BT/PR6646/MED/12/257/2005) to MDB, and a core grant from the Department of Biotechnology, Government of India to the Centre for DNA Fingerprinting and Diagnostics.

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Correspondence to Murali D. Bashyam.

Electronic supplementary material

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11010_2011_1077_MOESM1_ESM.doc

Figure S1. Blocks of multiple sequence alignments (MSAs) of human MYBPC3 with orthologues from other species. The MSAs were performed using ClustalW as described in the “Materials and methods” section and only those blocks of MSAs are shown where mutations were detected. The status of residues E710 and G758, C1124, W1214, and L1219 are shown. The sequences are: gi|148342489, Homo sapiens; gi|114326339, Canis lupus familiaris; gi|194217890, Equus caballus; gi|115495853, Bos taurus; gi|297688793, Pongo abelii; gi|297267981, Macaca mulatta; gi|291384958, Oryctolagus cuniculus; gi|134031947, Mus musculus; gi|157824043, Rattus norvegicus; gi|148233421, Xenopus laevis; gi|163915017, Xenopus (Silurana) tropicalis; gi|172072588, Danio rerio; gi|6166593, MYPC3_CHICK (DOC 36 kb)

11010_2011_1077_MOESM2_ESM.doc

Figure S2. Blocks of multiple sequence alignments (MSAs) of human MYH7 with the corresponding myosin chains from other species. The MSAs were performed using ClustalW as described in the “Materials and methods” section and only those blocks of the MSAs are shown that correspond to the regions of interest. The status of residues S322, M659, and R663 are shown. The sequences are: gi|115496169, Homo sapiens; gi|41386711, Bos taurus; gi|125987844, MYH7_PIG; gi|126352320, Equus caballus; gi|297694763, Pongo abelii; gi|296214577, Callithrix jacchus; gi|291403583, Oryctolagus cuniculus; gi|165973990, Canis lupus; gi|3041708, Mesocricetus auratus; gi|18859641, Mus musculus; gi|149063941, Rattus norvegicus; gi|126277437, Monodelphis domestica; gi|281342028, Ailuropoda melanoleuca; gi|297297517, Macaca mulatta; gi|11276954, Coturnix coturnix; gi|50838836, Gallus gallus; gi|148229072, Xenopus laevis; gi|87116414, Cyprinus carpio; gi|189536977, Danio rerio; gi|47208995, Tetraodon nigroviridis; gi|294489339, Oryzias latipes; gi|38347761, Lethenteron japonicum; gi|224074801, Taeniopygia guttata; gi|114669064, Pan troglodytes; gi|55742224, Xenopus (Silurana); gi|171702770, Coryphaenoides acrolepis; gi|171702772, Coryphaenoides cinereus; gi|171702768, Coryphaenoides armatus; gi|171702766, Coryphaenoides yaquinae; gi|134122720, Saurida undosquamis; gi|134122722, Saurida wanieso; gi|9971579, Pennahia argentata; gi|218546789, Sander vitreus; gi|21623523, Oncorhynchus keta; gi|41350446, Siniperca chuatsi; gi|129563832, Siniperca knerii; gi|7209643, Seriola dumerili; gi|15384839, Paracirrhites forsteri; gi|226434435, Takifugu rubripes; gi|160332463, Hypophthalmichthys molitrix; gi|12657354, Notothenia coriiceps (DOC 36 kb)

11010_2011_1077_MOESM3_ESM.tif

Figure S3A. Electropherograms showing known mutations detected in MYBPC3 among Indian FHC patients. A, c.821+1G>A (IVS7+1G>A); B, c.2273G>A (p.G758D); C, c.2905+1G>A (IVS26+1G>A); D, c.3372C>A (p.C1124X); and E, c.3628-24_48del25 (IVS31-24del25). For each, electropherogram showing the mutation is on the left side and the one showing the normal sequence is on the right side. Each mutation is indicated by an arrow; in A, the deleted base is indicated in the normal sequence. The electropherogram for c.3628-24_48del25 was obtained from cloned PCR product. In E, the Bar above the electropherogram for the normal sequence, indicates the 25 nucleotides that are deleted in the patient sample. (TIFF 182 kb)

11010_2011_1077_MOESM4_ESM.tif

Figure S3B. Electropherograms showing known mutations detected in MYH7 among Indian FHC patients. A, c.1977G>A (p.M659I), B, c.1988G>A (p.R663H) and C, c.2360G>A (p.R787H). For each, Electropherogram showing the mutation is on the left side and the one showing the normal sequence is on the right side. Each mutation is indicated by an arrow. (TIFF 150 kb)

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Bashyam, M.D., Purushotham, G., Chaudhary, A.K. et al. A low prevalence of MYH7/MYBPC3 mutations among Familial Hypertrophic Cardiomyopathy patients in India. Mol Cell Biochem 360, 373–382 (2012). https://doi.org/10.1007/s11010-011-1077-x

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Keywords

  • Hypertrophic cardiomyopathy
  • MYBPC3
  • MYH7
  • Mutation