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High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians  [cached]
Rani Deepa,Nallari Pratibha,Priyamvada Singh,Narasimhan Calambur
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-69
Abstract: Background Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. Methods We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. Results Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. Conclusion Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases  [cached]
Annapurna S,Reena T,Nallari Pratibha,Calambur Narasimhan
Indian Journal of Human Genetics , 2007,
Abstract: Background: Cardiomyopathies are a heterogeneous group of heart muscle disorders and are classified as 1) Hypertrophic Cardiomyopathy (HCM) 2) Dilated cardiomyopathy (DCM) 3) Restrictive cardiomyopathy (RCM) and 4) Arrhythmogenic right ventricular dysplasia (ARVD) as per WHO classification, of which HCM and DCM are common. HCM is a complex but relatively common form of inherited heart muscle disease with prevalence of 1 in 500 individuals and is commonly associated with sarcomeric gene mutations. Cardiac muscle troponin I (TNNI-3) is one such sarcomeric protein and is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. Mutations in this gene were found to be associated with a history of sudden cardiac death in HCM patients. Aim: Therefore the present study aims to identify for mutations associated with troponin I gene in a set of HCM patients from Indian population. Materials and Methods: Mutational analyses of 92 HCM cases were carried out following PCR based SSCP analysis. Results: The study revealed band pattern variation in 3 cases from a group of 92 HCM patients. This band pattern variation, on sequencing revealed base changes, one at nt 2560 with G>T transversion in exon-5 region with a wobble and others at nt 2479 and nt 2478 with G>C and C>G transversions in the intronic region upstream of the exon 5 on sequencing. Further analysis showed that one of the probands showed apical form of hypertrophy, two others showing asymmetric septal hypertrophy. Two of these probands showed family history of the condition. Conclusions: Hence, the study supports earlier reports of involvement of TNNI-3 in the causation of apical and asymmetrical forms of hypertrophy.
Cardiac Troponin Mutations and Restrictive Cardiomyopathy
Michelle S. Parvatiyar,Jose Renato Pinto,David Dweck,James D. Potter
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/350706
Abstract: Mutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, -actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants have established phenotypes consistent with the clinical findings which include an increase in myofilament Ca2
Troponin I release at rest and after exercise in patients with hypertrophic cardiomyopathy and the effect of betablockade
AM Pop, Gheorghe;Cramer, Etienne;Timmermans, Janneke;Bos, Hans;Verheugt, Freek WA;
Archivos de cardiología de México , 2006,
Abstract: purpose of the work: in patients with hypertrophic cardiomyopathy ischemia may occur due to massive heart weight, myocyte disarray or small vessel disease. we detected elevated troponin levels in some of these patients and hypothesized that troponin release would rise after exercise and diminish after betablockade. methods and results: in 5 of 7 young patients (6 males) with hypertrophic cardiomyopathy and no overt coronary artery disease we found elevated troponin levels after physical exercise; the peak was between 6 and 9 hours and levels returned to pre-exercise values within 24 hours. troponin release was consistently diminished after use of a betablocker. conclusions: increased troponin release may be present in patients with hypertrophic cardiomyopathy and is temporarily enhanced by exercise and diminishes with betablockade.
Effects of Troponin T Cardiomyopathy Mutations on the Calcium Sensitivity of the Regulated Thin Filament and the Actomyosin Cross-Bridge Kinetics of Human β-Cardiac Myosin  [PDF]
Ruth F. Sommese, Suman Nag, Shirley Sutton, Susan M. Miller, James A. Spudich, Kathleen M. Ruppel
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083403
Abstract: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) lead to significant cardiovascular morbidity and mortality worldwide. Mutations in the genes encoding the sarcomere, the force-generating unit in the cardiomyocyte, cause familial forms of both HCM and DCM. This study examines two HCM-causing (I79N, E163K) and two DCM-causing (R141W, R173W) mutations in the troponin T subunit of the troponin complex using human β-cardiac myosin. Unlike earlier reports using various myosin constructs, we found that none of these mutations affect the maximal sliding velocities or maximal Ca2+-activated ADP release rates involving the thin filament human β-cardiac myosin complex. Changes in Ca2+ sensitivity using the human myosin isoform do, however, mimic changes seen previously with non-human myosin isoforms. Transient kinetic measurements show that these mutations alter the kinetics of Ca2+ induced conformational changes in the regulatory thin filament proteins. These changes in calcium sensitivity are independent of active, cycling human β-cardiac myosin.
Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy
María Rodríguez-García, Lorenzo Monserrat, Martín Ortiz, Xusto Fernández, Laura Cazón, Lucía Nú?ez, Roberto Barriales-Villa, Emilia Maneiro, Elena Veira, Alfonso Castro-Beiras, Manuel Hermida-Prieto
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-67
Abstract: Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder, characterized by unexplained left ventricular hypertrophy, myocyte hypertrophy and disarray, and interstitial fibrosis [1,2]. It has a frequency of 0.2% in the adult population and is a major cause of sudden cardiac death (SD) in young people (< 35 years old). Ever since the first mutation in the beta myosin heavy chain (MYH7) gene was described as a cause of hypertrophic cardiomyopathy (HCM) in 1990 [3], mutations have been identified in 11 genes that codify cardiac sarcomeric proteins [4-7]. Genes that more frequently show mutations are MYH7 and the cardiac myosin binding protein C (MyBPC3) on chromosomes 14 and 11, respectively. Mutations in MyBPC3 are responsible for 15-20% of cases of familial HCM
Facilitated Cross-Bridge Interactions with Thin Filaments by Familial Hypertrophic Cardiomyopathy Mutations in α-Tropomyosin
Fang Wang,Nicolas M. Brunet,Justin R. Grubich,Ewa A. Bienkiewicz,Thomas M. Asbury,Lisa A. Compton,Goran Mihajlovi ,Victor F. Miller,P. Bryant Chase
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/435271
Abstract: Familial hypertrophic cardiomyopathy (FHC) is a disease of cardiac sarcomeres. To identify molecular mechanisms underlying FHC pathology, functional and structural differences in three FHC-related mutations in recombinant α-Tm (V95A, D175N, and E180G) were characterized using both conventional and modified in vitro motility assays and circular dichroism spectroscopy. Mutant Tm's exhibited reduced α-helical structure and increased unordered structure. When thin filaments were fully occupied by regulatory proteins, little or no motion was detected at pCa 9, and maximum speed (pCa 5) was similar for all tropomyosins. Ca2
Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene
Philipp Ehlermann, Dieter Weichenhan, J?rg Zehelein, Henning Steen, Regina Pribe, Raphael Zeller, Stephanie Lehrke, Christian Zugck, Boris T Ivandic, Hugo A Katus
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-95
Abstract: 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.Hypertrophic cardiomyopathy (HCM) is a common disease with an estimated prevalence of 1:500 in north americans [1]. The disease may remain without clinical symptoms for many years. HCM has been recognized as the most common cause of sudden cardiac death in the young, especially in competitive athletes, where it accounts for 26% of cases [2]. Therefore, early diagnosis is crucial for prevention of such catastrophic events. For risk stratification, an expert based recommendation exists, which is mainly based on clinical findings such as maximum wall t
How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance
Tjeerd Germans, Iris K Rüssel, Marco JW G?tte, Marieke D Spreeuwenberg, Pieter A Doevendans, Yigal M Pinto, Rob J van der Geest, Jolanda van der Velden, Arthur AM Wilde, Albert C van Rossum
Journal of Cardiovascular Magnetic Resonance , 2010, DOI: 10.1186/1532-429x-12-13
Abstract: 28 carriers and 28 controls were studied. Global left atrial (LA) and left ventricular (LV) dimensions, segmental peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR), as well as the presence of late Gadolinium enhancement (LGE) were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. lv mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio) was larger in carriers than in controls (1.3 ± 0.2 versus 1.1 ± 0.1, p < 0.001). Also, LA volumes were larger in carriers compared to controls (p < 0.05). Both peak SCS (p < 0.05) and peak DCSR (p < 0.01) were lower in carriers compared to controls, particularly in the basal lateral wall. Focal LGE was present in 2 carriers and not in controls. The combination of a SL ratio >1.2 and a peak DCSR <105%.s-1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio < 1.2 and peak DCSR >105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR.HCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.Hypertrophic cardiomyopathy (HCM) is a relatively common cardiomyopathy with an estimated prevalence of 1:500 in the general population [1]. The clinical course has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death
Cardiomyopathy-Related Mutations in Cardiac Troponin C, L29Q and G159D, Have Divergent Effects on Rat Cardiac Myofiber Contractile Dynamics  [PDF]
Sampath K. Gollapudi,Murali Chandra
Biochemistry Research International , 2012, DOI: 10.1155/2012/824068
Abstract: Previous studies of cardiomyopathy-related mutations in cardiac troponin C (cTnC)—L29Q and G159D—have shown diverse findings. The link between such mutant effects and their divergent impact on cardiac phenotypes has remained elusive due to lack of studies on contractile dynamics. We hypothesized that a cTnC mutant-induced change in the thin filament will affect global myofilament mechanodynamics because of the interactions of thin filament kinetics with both C a 2 + binding and crossbridge (XB) cycling kinetics. We measured pCa-tension relationship and contractile dynamics in detergent-skinned rat cardiac papillary muscle fibers reconstituted with the recombinant wild-type rat cTnC ( c T n C W T ), c T n C L 2 9 Q , and c T n C G 1 5 9 D mutants. c T n C L 2 9 Q fibers demonstrated a significant decrease in C a 2 + sensitivity, but c T n C G 1 5 9 D fibers did not. Both mutants had no effect on C a 2 + -activated maximal tension. The rate of XB recruitment dynamics increased in c T n C L 2 9 Q (26%) and c T n C G 1 5 9 D (25%) fibers. The rate of XB distortion dynamics increased in c T n C G 1 5 9 D fibers (15%). Thus, the c T n C L 2 9 Q mutant modulates the equilibrium between the non-cycling and cycling pool of XB by affecting the on/off kinetics of the regulatory units (Tropomyosin-Troponin); whereas, the c T n C G 1 5 9 D mutant increases XB cycling rate. Different effects on contractile dynamics may offer clue regarding how c T n C L 2 9 Q and c T n C G 1 5 9 D cause divergent effects on cardiac phenotypes. 1. Introduction The presumptive conclusion drawn from the heterogenic nature of human cardiomyopathy suggests a link between the type of mutation and the nature of pathological remodeling of the heart. A growing number of mutations in human cardiac troponin C (cTnC), associated with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), makes it a prominent target gene for functional characterization. Thus far, 5 mutations in cTnC are found to be associated with HCM and 6 with DCM. These HCM-linked cTnC mutations include L29Q [1]—A8V, C84Y, and E134D [2]—Q122AfsX30 [3], while the DCM-linked cTnC mutations include E59D/D75Y [4], G159D [5]—Y5H, M103I, D145E, and I148V [6]. cTnC comprises two globular lobes; the amino-(N) and the carboxyl-(C) terminal lobes, which are connected by a flexible linker. The binding of C a 2 + to the regulatory site-II of the N-lobe of cTnC is important for triggering structural changes in the regulatory unit (RU), consisting of troponin (Tn) and tropomyosin (Tm). The binding of C a 2 + to cTnC has a
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