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Michael Christiansen - One of the best experts on this subject based on the ideXlab platform.
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A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity
Biochemistry research international, 2012Co-Authors: Paal Skytt Andersen, Johanna C. Moolman-smook, Petros Syrris, William J Mckenna, Perry M Elliott, Paula L Hedley, Stephen P. Page, Michael ChristiansenAbstract:Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset.
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the role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy
European Journal of Human Genetics, 2009Co-Authors: Daniel V Moller, Paal Skytt Andersen, Henning Bundgaard, Michael Christiansen, Paula L Hedley, Mads Ersboll, Johanna C Moolmansmook, Lars KoberAbstract:We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.
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High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.
Electrophoresis, 2005Co-Authors: Huijun Tian, Paal Skytt Andersen, Lars Allan Larsen, Charles A. Emrich, James R. Scherer, Richard A. Mathies, Michael ChristiansenAbstract:A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.
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High-throughput single strand conformation polymorphism mutation detection by automated capillary array electrophoresis: validation of the method.
Human mutation, 2003Co-Authors: Paal Skytt Andersen, Michael Christiansen, Cathrine Jespersgaard, Jens Vuust, Lars Allan LarsenAbstract:Capillary array electrophoresis (CAE) is a novel technique, which allows for high throughput analysis of DNA fragments. When screening for mutations in whole populations or large patient groups it is necessary to have robust and well-characterized setups for high throughput analysis. For large-scale mutation screening, we have developed procedures for single strand conformation polymorphism (SSCP) assays using CAE (CAE-SSCP) whereby we may increase both the sensitivity and the throughput compared to conventional SSCP analysis. In this study we have validated CAE-SSCP by 1) comparing detection by slab-gel based SSCP with CAE-SSCP of mutations in the MYH7, MYL2, and MYL3 genes encoding sarcomere proteins from patients suffering from hypertrophic cardiomyopathy; and 2) by constructing a series of 185 mutants having substitution mutations, as well as insertion/deletion mutations, or some combinations of these, in different sequence contexts in four exons and different positions relative to the end of the amplicon (three from the KCNQ1 gene, encoding a cardiac potassium channel, and one from the TNNI3 gene encoding cardiac troponin I). The method identified 181 out of 185 mutations (98%), and the data suggest that the position of mutation in the fragment had no effect on the sensitivity. Analysis of the specificity of the method showed that only very few mutants could not be distinguished from each other and there were no false positives.
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Development and application of linkage analysis in genetic diagnosis of familial hypertrophic cardiomyopathy
Journal of medical genetics, 2001Co-Authors: Jens Mogensen, Paal Skytt Andersen, Michael Christiansen, Henrik Egeblad, Ulla Steffensen, Niels Gregersen, Anders D. BørglumAbstract:Editor—Familial hypertrophic cardiomyopathy (FHC) is a prevalent dominantly inherited disease characterised by unexplained hypertrophy of the heart muscle. The clinical manifestations are heterogeneous and the disease is a leading cause of sudden cardiac death among young, otherwise healthy people.1 More than 120 different mutations have been reported in the following eight genes encoding sarcomeric polypeptides given in parentheses: TNNT2 (troponin T), MYL3 (essential myosin light chain), MYH7 (β myosin heavy chain), MYBPC3 (myosin binding protein C), MYL2 (regulatory myosin light chain), TPM1 (α tropomyosin), ACTC (α cardiac actin), and TNNI3 (troponin I).2 3Furthermore, a disease locus on chromosome 7 has been linked to FHC, but the gene has not yet been identified.4 Additional disease genes probably remain to be discovered since two recent studies found that it was only possible to genotype 50-60% of the FHC population by mutation analyses of seven disease genes.5 6 In order to optimise risk stratification and management of FHC patients, it is important to identify all disease carriers, which is difficult by physical examination because of the age dependent penetrance of the disease. However, disease carriers may be identified by use of genetic diagnosis, although it is laborious because of the large number of disease genes and the pronounced allelic heterogeneity of the disease loci, with the majority of affected families having their own “private” missense mutation.7 In addition, genetic diagnosis is complicated by the fact that several amino acid polymorphisms occur in most of the FHC genes8 9 (unpublished observations). Given this complex genetic background, the use of linkage analysis can be beneficial as it may identify the most likely disease gene and provide evidence for exclusion of some or all of the other candidate disease loci even in small families.10 It was …
Paal Skytt Andersen - One of the best experts on this subject based on the ideXlab platform.
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A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity
Biochemistry research international, 2012Co-Authors: Paal Skytt Andersen, Johanna C. Moolman-smook, Petros Syrris, William J Mckenna, Perry M Elliott, Paula L Hedley, Stephen P. Page, Michael ChristiansenAbstract:Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset.
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the role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy
European Journal of Human Genetics, 2009Co-Authors: Daniel V Moller, Paal Skytt Andersen, Henning Bundgaard, Michael Christiansen, Paula L Hedley, Mads Ersboll, Johanna C Moolmansmook, Lars KoberAbstract:We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.
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High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.
Electrophoresis, 2005Co-Authors: Huijun Tian, Paal Skytt Andersen, Lars Allan Larsen, Charles A. Emrich, James R. Scherer, Richard A. Mathies, Michael ChristiansenAbstract:A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.
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Clinical and genetic characteristics of alpha cardiac actin gene mutations in hypertrophic cardiomyopathy
Journal of medical genetics, 2004Co-Authors: Jens Mogensen, Andreas Perrot, Paal Skytt Andersen, Ole Havndrup, Henning Bundgaard, I C Klausen, Morten Krogh Christiansen, Peter Bross, Henrik Egeblad, K J OsterzielAbstract:Hypertrophic cardiomyopathy (HCM) is a dominantly inherited disease defined by unexplained myocardial hypertrophy. The prevalence is about 0.2% in the general population. The condition is characterised by a heterogeneous disease expression, and common symptoms include angina, dyspnoea, palpitations, syncope, and exercise limitation. Hypertrophic cardiomyopathy is a frequent cause of sudden cardiac death in young people.1 More than 200 mutations associated with the disease have been identified in sarcomeric contractile protein genes: TNNT2 (troponin T), MYL3 (essential myosin light chain), MYBPC3 (myosin binding protein C), MYL2 (regulatory myosin light chain), MYH7 (β myosin heavy chain), TPM1 (α tropomyosin), ACTC (α cardiac actin), and TNNI3 (troponin I).2–4 In addition, mutations recently have been reported in two non-sarcomeric genes.5–7 Mutations in ACTC have also been reported to cause the inherited form of idiopathic dilated cardiomyopathy (DCM). It has been suggested previously that ACTC mutations that affect sarcomere contraction lead to HCM, whereas ACTC mutations that affect force transmission from the sarcomere to the surrounding syncytium lead to DCM.3,8 We report the clinical and genetic characteristics of ACTC mutations in 206 consecutive patients with HCM. Informed consent was obtained from each participant in accordance with local institutional review committee guidelines. We investigated 206 consecutive Caucasian probands with HCM from Germany (n = 146) or Denmark (n = 60) by mutation analysis of ACTC . We physically and genetically investigated relatives of probands who carried ACTC mutations. The diagnosis of HCM was based on the presence of unexplained myocardial hypertrophy.3,9,10 In brief, a person was defined as having HCM if the maximal left ventricular wall thickness by echocardiography or cardiac magnetic resonance scan was ⩾13 mm or the electrocardiogram (ECG) showed major Q wave abnormalities, left ventricular hypertrophy, or marked repolarisation alterations. One patient (pedigree B, participant I-1) was …
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High-throughput single strand conformation polymorphism mutation detection by automated capillary array electrophoresis: validation of the method.
Human mutation, 2003Co-Authors: Paal Skytt Andersen, Michael Christiansen, Cathrine Jespersgaard, Jens Vuust, Lars Allan LarsenAbstract:Capillary array electrophoresis (CAE) is a novel technique, which allows for high throughput analysis of DNA fragments. When screening for mutations in whole populations or large patient groups it is necessary to have robust and well-characterized setups for high throughput analysis. For large-scale mutation screening, we have developed procedures for single strand conformation polymorphism (SSCP) assays using CAE (CAE-SSCP) whereby we may increase both the sensitivity and the throughput compared to conventional SSCP analysis. In this study we have validated CAE-SSCP by 1) comparing detection by slab-gel based SSCP with CAE-SSCP of mutations in the MYH7, MYL2, and MYL3 genes encoding sarcomere proteins from patients suffering from hypertrophic cardiomyopathy; and 2) by constructing a series of 185 mutants having substitution mutations, as well as insertion/deletion mutations, or some combinations of these, in different sequence contexts in four exons and different positions relative to the end of the amplicon (three from the KCNQ1 gene, encoding a cardiac potassium channel, and one from the TNNI3 gene encoding cardiac troponin I). The method identified 181 out of 185 mutations (98%), and the data suggest that the position of mutation in the fragment had no effect on the sensitivity. Analysis of the specificity of the method showed that only very few mutants could not be distinguished from each other and there were no false positives.
Lars Allan Larsen - One of the best experts on this subject based on the ideXlab platform.
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High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.
Electrophoresis, 2005Co-Authors: Huijun Tian, Paal Skytt Andersen, Lars Allan Larsen, Charles A. Emrich, James R. Scherer, Richard A. Mathies, Michael ChristiansenAbstract:A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.
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High-throughput single strand conformation polymorphism mutation detection by automated capillary array electrophoresis: validation of the method.
Human mutation, 2003Co-Authors: Paal Skytt Andersen, Michael Christiansen, Cathrine Jespersgaard, Jens Vuust, Lars Allan LarsenAbstract:Capillary array electrophoresis (CAE) is a novel technique, which allows for high throughput analysis of DNA fragments. When screening for mutations in whole populations or large patient groups it is necessary to have robust and well-characterized setups for high throughput analysis. For large-scale mutation screening, we have developed procedures for single strand conformation polymorphism (SSCP) assays using CAE (CAE-SSCP) whereby we may increase both the sensitivity and the throughput compared to conventional SSCP analysis. In this study we have validated CAE-SSCP by 1) comparing detection by slab-gel based SSCP with CAE-SSCP of mutations in the MYH7, MYL2, and MYL3 genes encoding sarcomere proteins from patients suffering from hypertrophic cardiomyopathy; and 2) by constructing a series of 185 mutants having substitution mutations, as well as insertion/deletion mutations, or some combinations of these, in different sequence contexts in four exons and different positions relative to the end of the amplicon (three from the KCNQ1 gene, encoding a cardiac potassium channel, and one from the TNNI3 gene encoding cardiac troponin I). The method identified 181 out of 185 mutations (98%), and the data suggest that the position of mutation in the fragment had no effect on the sensitivity. Analysis of the specificity of the method showed that only very few mutants could not be distinguished from each other and there were no false positives.
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Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations
Journal of medical genetics, 2001Co-Authors: Paal Skytt Andersen, Ole Havndrup, Henning Bundgaard, Johanna C. Moolman-smook, Lars Allan Larsen, Jens Mogensen, Paul A. Brink, Anders D. Børglum, Valerie A. Corfield, Keld KjeldsenAbstract:Editor—Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which may afflict as many as 1 in 500 subjects.1 The disease is characterised by an unexplained local or general myocardial hypertrophy and by myocyte disarray.2 Molecular genetic studies have so far identified nine disease associated genes, all of which encode sarcomeric proteins. The two genes in which most mutations have been described are the β-myosin heavy chain ( MYH7 )3 and the myosin binding protein C ( MYBPC3 ) genes,4 each of which may account for up to 30% of all familial cases. Mutations in α-tropomyosin ( TPM1 ),5troponin T ( TNNT2 ),5 6troponin I ( TNNI3 ),6 cardiac α-actin ( ACTC ),7 titin ( TTN ),8 and the essential ( MYL3 ) and the regulatory ( MYL2 ) myosin light chain genes have also been associated with FHC.9 This pronounced genetic heterogeneity may be the principal cause of the phenotypic variability that is seen in FHC. Thus, mutations in TNNT2 seem to be associated with sudden death at a young age,10 11 whereas families with mutations in MYBPC3 are generally characterised by progressive hypertrophy and a late onset of clinical manifestation.12 13 Furthermore, it has been proposed that a certain rare form of hypertrophic cardiomyopathy (HCM), asymmetric septal hypertrophy predominantly confined to the midventricular region, known as the midventricular hypertrophy (MVH) phenotype, may be associated with mutations in the two myosin light chain genes.9 However, limited and contradictory clinical information is available on FHC caused by mutations in these genes.9 14 We have studied MYL2 and MYL3 in 68 consecutively collected FHC families from Denmark and in 130 probands from South Africa. We established the frequency of myosin light chain mutations and assessed whether mutations in these two genes do cause a distinct …
Kumarasamy Thangaraj - One of the best experts on this subject based on the ideXlab platform.
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Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies
Indian Journal of Cardiovascular Disease in Women WINCARS, 2019Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Kumarasamy ThangarajAbstract:Abstract 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.
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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.
Cardiology, 2018Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Nizamuddin, Thulasamma Seelamneni, Calambur Narasimhan, Kumarasamy ThangarajAbstract:Background Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes - 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. Objectives Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. Method For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. Results Our study revealed a total of 10 variations - 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. Conclusions MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.
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Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM
DNA and cell biology, 2015Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Calambur Narasimhan, Perundurai S. Dhandapany, Khunza Meraj, Mala Ganesan, Kumarasamy ThangarajAbstract:Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases—patient #1, aged 44, and patient #2, aged 65—and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. I...
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A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM)
PloS one, 2014Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Perundurai S. Dhandapany, Kumarasamy ThangarajAbstract:Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
Deepa Selvi Rani - One of the best experts on this subject based on the ideXlab platform.
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Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies
Indian Journal of Cardiovascular Disease in Women WINCARS, 2019Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Kumarasamy ThangarajAbstract:Abstract 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.
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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.
Cardiology, 2018Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Nizamuddin, Thulasamma Seelamneni, Calambur Narasimhan, Kumarasamy ThangarajAbstract:Background Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes - 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. Objectives Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. Method For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. Results Our study revealed a total of 10 variations - 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. Conclusions MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.
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Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM
DNA and cell biology, 2015Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Jhansi Rani, Calambur Narasimhan, Perundurai S. Dhandapany, Khunza Meraj, Mala Ganesan, Kumarasamy ThangarajAbstract:Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases—patient #1, aged 44, and patient #2, aged 65—and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. I...
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A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM)
PloS one, 2014Co-Authors: Deepa Selvi Rani, Pratibha Nallari, Calambur Narasimhan, Perundurai S. Dhandapany, Kumarasamy ThangarajAbstract:Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
