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1.  Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases 
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.
doi:10.4103/0971-6866.34706
PMCID: PMC3168158  PMID: 21957345
Genetic variation; hypertrophic cardiomyopathy; sudden cardiac death; troponin-I
2.  Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy 
Netherlands Heart Journal  2011;19(7-8):344-351.
Background
About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.
Methods
TheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes.
Results
In 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non-familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p.Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis.
Conclusion
In line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation.
doi:10.1007/s12471-011-0135-z
PMCID: PMC3144325  PMID: 21533915
TNNI3; Founder; HCM; RCM; DCM
3.  Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy 
Netherlands Heart Journal  2011;19(7-8):344-351.
Background
About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.
Methods
TheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes.
Results
In 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non-familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p.Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis.
Conclusion
In line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation.
doi:10.1007/s12471-011-0135-z
PMCID: PMC3144325  PMID: 21533915
TNNI3; Founder; HCM; RCM; DCM
4.  A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM) 
PLoS ONE  2014;9(7):e101451.
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.
doi:10.1371/journal.pone.0101451
PMCID: PMC4081629  PMID: 24992688
5.  Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations 
Circulation research  2013;112(11):1491-1505.
Rationale
High-myofilament Ca2+-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca2+-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce.
Objective
To investigate whether high-myofilament Ca2+-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins.
Methods and Results
Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca2+-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca2+-sensitivity was either similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.
Conclusions
High-myofilament Ca2+-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a common pathomechanism in HCM.
doi:10.1161/CIRCRESAHA.111.300436
PMCID: PMC3675884  PMID: 23508784
calcium; cardiomyopathy; contractility; hypertrophy; myocardium
6.  An In Silico Analysis of Troponin I Mutations in Hypertrophic Cardiomyopathy of Indian Origin 
PLoS ONE  2013;8(8):e70704.
Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.
doi:10.1371/journal.pone.0070704
PMCID: PMC3742764  PMID: 23967088
7.  Coexistence of mitochondrial DNA and β myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure 
Heart  1998;80(6):548-558.
Objective—To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with β myosin heavy chain (βMHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure.
Design—Molecular analysis of βMHC and mtDNA gene defects in patients with HCM.
Setting—Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy.
Patients—Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy.
Intervention—Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens.
Main outcome measures—Screening for mutations in βMHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing.
Results—One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) βMHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel βMHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C.
Conclusions—βMHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although βMHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in βMHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM.

 Keywords: β myosin heavy chain;  mitochondrial DNA;  hypertrophic cardiomyopathy;  oxidative phosphorylation;  congestive heart failure
PMCID: PMC1728869  PMID: 10065021
8.  Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. 
Heart  1996;76(1):63-65.
OBJECTIVE: The disease-bearing genes for hypertrophic cardiomyopathy (HCM) in HCM families have been identified as the beta-myosin heavy chain, alpha-tropomyosin, and cardiac troponin T genes. Three HCM kindreds with three distinct point mutations in the alpha-tropomyosin gene had extensive clinical evaluations. DESIGN AND RESULTS: Single-strand conformation polymorphism gel analysis of polymerase chain reaction amplified products was used to capture each of the nine exons from the alpha-tropomyosin gene to identify mutations in 60 familial HCM patients. Two missense mutations in exon 2 (Ala63Val and Lys70Thr) and one missense mutation in exon 5 (Asp175Asn) were found in three unrelated HCM kindreds. These kindreds were the subject of clinical, electrocardiographic and echocardiographic studies. The morphological appearance of HCM was similar in the three kindreds. All the patients had severe hypertrophy of the left ventricle with asymmetrical septal hypertrophy during the early stage of the disease, which gradually progressed to dilatation of the left ventricle. Moreover, these kindreds showed similar disease penetrance, age of onset, and incidence of premature sudden death. The disease in these kindreds was severe and resulted in frequent sudden deaths. CONCLUSIONS: Among Japanese patients with familial HCM mutations in the alpha-tropomyosin gene are not as rare as reported, accounting for about 5% of all cases. These mutations are characterised by hypertrophy of the left ventricle which then progresses to dilatation and a high incidence of sudden or disease-related death.
PMCID: PMC484428  PMID: 8774330
9.  Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations 
Journal of Clinical Investigation  2003;111(2):209-216.
Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene.
doi:10.1172/JCI200316336
PMCID: PMC151864  PMID: 12531876
10.  MYBPC3 gene variations in hypertrophic cardiomyopathy patients in India 
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is a complex cardiac muscular disorder, inherited as an autosomal dominant disease with variable penetrance. Cardiac myosin-binding protein C (MyBPC) is the predominant myosin-binding protein isoform in the heart muscle. One hundred forty-seven mutations have been detected in MYBPC3, accounting for 15% of all HCM cases.
OBJECTIVE
To screen exons 16, 18, 19, 22, 24, 28, 30, 31 and 34 in the MYBPC3 gene in Indian HCM patients.
METHODS
Sixty control and 95 HCM samples were collected from cardiology units of the CARE Hospital (Nampally, Banjara Hills, Secunderabad, India) for genomic DNA isolation followed by polymerase chain reaction and single-stranded conformational polymorphism analysis.
RESULTS
Screening of the exons revealed two variations – one novel frame shift mutation in exon 19 at the nucleotide position 11577^11578 and one novel single nucleotide polymorphism (SNP) in codon 1093 of exon 31, coding for glycine with a C>T transition (GGC/GGT), in addition to the seven known SNPs mainly in the intronic region and one known missense mutation D770N in this population.
CONCLUSION
The novel frame shift mutation identified in exon 19, D570fs, with the insertion of an adenine residue in codon 570 coding for aspartate, results in a premature termination codon that produces a truncated protein lacking myosin- and titin-binding sites, explaining the role of the nonsense-mediated decay pathway. A novel SNP identified in codon 1093 of exon 31 was found to be a synonymous codon, which may have a regulatory effect at the translational level, attributing to affinity differences between codon-anticodon interactions. The screening of this gene may be relevant in the Indian context.
PMCID: PMC2644567  PMID: 18273486
Hypertrophic cardiomyopathy; MYBPC3; Nonsense-mediated decay pathway; Novel mutation
11.  ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE study) 
Netherlands Heart Journal  2013;21(12):567-571.
Introduction
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM.
Methods
Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group.
Endpoints
Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.
doi:10.1007/s12471-013-0478-8
PMCID: PMC3833912  PMID: 24114686
Hypertrophic cardiomyopathy; Carrier; Myocardial energetics; Sarcomere mutations
12.  Combined obstructive hypertrophic cardiomyopathy and double outlet right ventricle in an infant with Down syndrome 
Patient: Male, 2
Final Diagnosis: Obstructive hypertrophic cardiomyopathy
Symptoms: Congestive heart failure
Medication: —
Clinical Procedure: Left ventricular septal myectomy • repair of congenital heart disease
Specialty: Cardiology
Objective:
Rare disease
Background:
Hypertrophic cardiomyopathy (HCM) is uncommon in Down syndrome (DS). When combined with congenital heart disease (CHD) both morbidity and mortality may be greater compared to CHD alone. Whether HCM in DS patients is related to having trisomy 21 versus a second site mutation is unknown.
Case Report:
We report a case of severe HCM in an infant with DS in combination with double outlet right ventricle (DORV) who required surgery for relive of sub-aortic obstruction and congestive heart failure. We predicted that this infant would have a second site mutation involving either a sarcomeric protein or metabolic disorder as a cause for his HCM. Using current genetic and metabolic testing as well as histologic assessment of excised cardiac tissue we sought to further characterize the nature of the HCM. A successful resection of sub-aortic stenosis and DORV repair was performed. Genetic and metabolic testing was negative for gene defects and/or syndromes commonly associated with familial HCM. Excised cardiac tissue from the ventricular septum exhibited myocyte hypertrophy and sub-endocardial fibrosis but no sarcomeric disarray, myocyte fibrosis or glycogen storage. Metabolic testing for common forms of mitochondrial disease was negative. Post-operative echocardiograms show persistent, non-obstructive septal hypertrophy.
Conclusions:
Unlike prior reports, this child required a surgical intervention to relieve his sub-aortic obstruction. Thus, HCM in this population can be more serious that previously suspected. Although testing did not reveal the cause of his HCM, we still suggest screening for known causes of HSC until the etiology of the HCM in DS is well understood.
doi:10.12659/AJCR.889581
PMCID: PMC3821707  PMID: 24222815
conal-truncal defect; hypertrophic cardiomyopathy; Down syndrome
13.  Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene 
BMC Medical Genetics  2008;9:95.
Background
Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2350-9-95
PMCID: PMC2584029  PMID: 18957093
14.  Molecular and Functional Characterization of Novel Hypertrophic Cardiomyopathy Susceptibility Mutations in TNNC1- Encoded Troponin C 
Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes and has been associated with mutations in most sarcomeric proteins (tropomyosin, Troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca2+-sensitivity of contraction, a hallmark of HCM, and surprisingly, prior to this report, cTnC had not been classified as a HCM susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca2+ sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. These types of studies may help to further define TNNC1 as an HCM-susceptibility gene that has already been established for the other members of the Troponin complex.
doi:10.1016/j.yjmcc.2008.05.003
PMCID: PMC2627482  PMID: 18572189
troponin C; TnC; hypertrophic cardiomyopathy; HCM; mutation; calcium; genetics
15.  Relationship between sex, shape, and substrate in hypertrophic cardiomyopathy 
American heart journal  2008;155(6):1128-1134.
Background
Hypertrophic cardiomyopathy (HCM) is a disease characterized by substantial genetic, morphologic, and prognostic heterogeneity. Recently, sex-related differences in HCM were reported, with women being older at diagnosis and exhibiting greater left ventricular outflow tract obstruction than men. We sought to evaluate the influence of sex on the HCM phenotype in a large cohort of unrelated patients with genetically and morphologically classified HCM.
Methods
Comprehensive genotyping of 13 HCM-susceptibility genes encoding myofilament and Z-disc proteins of the cardiac sarcomere was performed previously on 382 unrelated patients with HCM. Blinded to the genotype, the septal morphology was graded as reverse-curvature, sigmoidal, apical, or neutral-contour HCM by echocardiography.
Results
Overall, women (a) were significantly older at diagnosis (45.1 ± 20 vs 35.8 ± 17 years, P < .001), (b) had greater left ventricular outflow tract obstruction (53.5 ± 45 vs 41.7 ± 42 mm Hg, P = .009), (c) were more likely to have concomitant hypertension (19% vs 11%, P = .02), and (d) had a higher rate of surgical myectomy (49% vs 36%, P = .01) than men. Interestingly, these sex-based differences were apparent only among patients with sigmoidal HCM (P < .001).
Conclusions
In this largest cohort of comprehensively genotyped and morphologically classified patients with clinically diagnosed HCM, we observed that the striking sex-related differences in the clinical phenotype are confined largely to the subset of mutation-negative sigmoidal HCM. Whereas mutations within the sarcomere appear to dominate the disease process, in their absence, sex has a significant modifying effect, specifically noted in cases of sigmoidal HCM.
doi:10.1016/j.ahj.2008.01.005
PMCID: PMC3912560  PMID: 18513529
16.  The novel mitochondrial 16S rRNA 2336T>C mutation is associated with hypertrophic cardiomyopathy 
Journal of Medical Genetics  2013;51(3):176-184.
Background
Hypertrophic cardiomyopathy (HCM) is a primary disorder characterised by asymmetric thickening of septum and left ventricular wall, with a prevalence of 0.2% in the general population.
Objective
To describe a novel mitochondrial DNA mutation and its association with the pathogenesis of HCM.
Methods and results
All maternal members of a Chinese family with maternally transmitted HCM exhibited variable severity and age at onset, and were implanted permanent pacemakers due to complete atrioventricular block (AVB). Nuclear gene screening (MYH7, MYBPC3, TNNT2 and TNNI3) was performed, and no potential pathogenic mutation was identified. Mitochondrial DNA sequencing analysis identified a novel homoplasmic 16S rRNA 2336T>C mutation. This mutation was exclusively present in maternal members and absent in non-maternal members. Conservation index by comparison to 16 other vertebrates was 94.1%. This mutation disturbs the 2336U-A2438 base pair in the stem–loop structure of 16S rRNA domain III, which is involved in the assembly of mitochondrial ribosome. Oxygen consumption rate of the lymphoblastoid cells carrying 2336T>C mutation had decreased by 37% compared with controls. A reduction in mitochondrial ATP synthesis and an increase in reactive oxidative species production were also observed. Electron microscopic analysis indicated elongated mitochondria and abnormal mitochondrial cristae shape in mutant cells.
Conclusions
It is suggested that the 2336T>C mutation is one of pathogenic mutations of HCM. This is the first report of mitochondrial 16S rRNA 2336T>C mutation and an association with maternally inherited HCM combined with AVB. Our findings provide a new insight into the pathogenesis of HCM.
doi:10.1136/jmedgenet-2013-101818
PMCID: PMC3932983  PMID: 24367055
17.  Mutations in the cardiac troponin T gene show various prognoses in Japanese patients with hypertrophic cardiomyopathy 
Heart and Vessels  2013;28:785-794.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder resulting from mutations in genes for at least 15 various sarcomere-related proteins including cardiac β-myosin heavy chain, cardiac myosin-binding protein C, and cardiac troponin T. The troponin T gene (TNNT2) mutation has the third incidence of familial HCM, and the genotype–phenotype correlation of this gene still remains insufficient in Japanese familial HCM. Therefore, in the present study, we focused on screening the TNNT2 mutation in 173 unrelated Japanese patients with familial HCM, and found three reported mutations and a new mutation of TNNT2 in 11 individuals from four families. In these families, two individuals from one family had double mutations, Arg130Cys and Phe110Ile, six individuals from two other families had an Arg92Trp mutation, and one individual of another family had a new mutation, Ile79Thr, of TNNT2. The phenotype of each family was often different from reported cases, even if they had the same genetic mutation. In addition, families with the same genetic mutation showed a similar trend in the phenotype, but it was not exactly the same. However, sudden death in youth was observed in all of these families. Although the type of genetic mutation is not useful for predicting prognosis in HCM, the possibility of sudden cardiac death remains. Therefore, the prognosis of individuals bearing the TNNT2 mutation with familial HCM should be more carefully observed from birth.
doi:10.1007/s00380-013-0332-3
PMCID: PMC3830204  PMID: 23494605
Familial hypertrophic cardiomyopathy; TNNT2 gene; Mutation; Phenotype–genotype
18.  Genotype—phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin ☆ 
Background
TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte’s stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.
Methods
DNA was obtained from 389 patients with HCM (215 male, left ventricular wall thickness of 21.6 ± 6 mm) and analyzed for mutations involving all translated exons of CSRP3 and TCAP and targeted HCM-associated exons (2, 3, 4, and 14) of TTN using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. Clinical data were extracted from patient records and maintained independent of the genotype.
Results
Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected. Seven patients were also found to have a concomitant myofilament mutation. Seven patients with a MLP-mutation were found to harbor the DCM-associated, functionally characterized W4R mutation. W4R-MLP was also noted in a single white control subject. Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM.
Conclusions
Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation.
doi:10.1016/j.ymgme.2005.10.008
PMCID: PMC2756511  PMID: 16352453
Genetics; Genes; Hypertrophy; Cardiomyopathy; Z-disc; Muscle LIM protein; Telethonin; TCAP; Titin
19.  High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort 
BMC Medical Genetics  2012;13:17.
Background
Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine.
Methodology
In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population.
Results
HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations.
Conclusions
HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations.
doi:10.1186/1471-2350-13-17
PMCID: PMC3359199  PMID: 22429680
Hypertrophic cardiomyopathy; Gene-based diagnosis; High Resolution Melting; Sarcomere proteins; CSRP3 gene
20.  Genetic variations of β-MYH7 in hypertrophic cardiomyopathy and dilated cardiomyopathy 
CONTEXT:
Hypertrophic cardiomyopathy (HCM) is known to be manifested by mutations in 12 sarcomeric genes and dilated cardiomyopathy (DCM) is known to manifest due to cytoskeletal mutations. Studies have revealed that sarcomeric mutations can also lead to DCM. Therefore, in the present study, we have made an attempt to compare and analyze the genetic variations of beta-myosin heavy chain gene (β-MYH7), which are interestingly found to be common in both HCM and DCM. The underlying pathophysiological mechanism leading to two different phenotypes has been discussed in this study. Till date, about 186 and 73 different mutations have been reported in HCM and DCM, respectively, with respect to this gene.
AIM:
The screening of β-MYH7 gene in both HCM and DCM has revealed some common genetic variations. The aim of the present study is to understand the pathophysiological mechanism underlying the manifestation of two different phenotypes.
MATERIALS AND METHODS:
100 controls, 95 HCM and 97 DCM samples were collected. Genomic DNA was extracted following rapid nonenzymatic method as described by Lahiri and Nurnberger (1991), and the extracted DNA was later subjected to polymerase chain reaction (PCR) based single stranded conformation polymorphism (SSCP) analysis to identify single nucleotide polymorphism (SNP)s/mutations associated with the diseased phenotypes.
RESULTS AND CONCLUSION:
Similar variations were observed in β-MYH7 exons 7, 12, 19 and 20 in both HCM and DCM. This could be attributed to impaired energy compromise, or to dose effect of the mutant protein, or to even environmental factors/modifier gene effects wherein an HCM could progress to a DCM phenotype affecting both right and left ventricles, leading to heart failure.
doi:10.4103/0971-6866.69348
PMCID: PMC2955954  PMID: 21031054
Diastolic dysfunction; dose effect; dilated cardiomyopathy; hypertrophic cardiomyopathy; single nucleotide polymorphism; systolic dysfunction
21.  Molecular genetics and pathogenesis of hypertrophic cardiomyopathy 
Minerva medica  2001;92(6):435-451.
Advances in molecular genetics of hypertrophic cardiomyopathy (HCM) have led to identification of mutations in 11 genes coding for sarcomeric proteins. In addition, mutations in gene coding for the γ subunit of AMP-activated protein kinase and triplet-repeat syndromes, as well as in mitochondrial DNA have been identified in patients with HCM. Mutations in genes coding for the β-myosin heavy chain, myosin binding protein-C, and cardiac troponin T account for approximately 2/3 of all HCM cases. Accordingly, HCM is considered a disease of contractile sarcomeric proteins. Genotype-phenotype correlation studies show mutations and the genetic background affect the phenotypic expression of HCM. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The molecular pathogenesis of HCM is not completely understood. The initial defects caused by the mutant proteins are diverse. However, despite their diversity, they converge into common final pathway of impaired cardiac myocyte function. The latter leads to an increased myocyte stress and subsequent activation of stress-responsive signaling kinases and trophic factors, which activate the transcriptional machinery inducing cardiac hypertrophy, interstitial fibrosis and myocyte disarray, the pathological characteristics of HCM. Studies in transgenic animal models show that cardiac hypertrophy, interstitial fibrosis, and myocyte disarray are potentially reversible. These findings raise the possibility of reversal of evolving phenotype or prevention of phenotypes in human patients with HCM. Elucidation of the molecular genetic basis and the pathogenesis of HCM could provide the opportunity for genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in those who have inherited the causal mutations for HCM.
PMCID: PMC2910253  PMID: 11740432
Cardiomyopathy; hypertrophic; genetics - Genes - Mutation - Death; sudden; cardiac
22.  Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy 
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca2+-activated force was much lower in HCM myocytes (14 ± 1 kN/m2) than in donor myocytes (23 ± 3 kN/m2; P < 0.01), though cross-bridge kinetics (ktr) during maximal Ca2+ activation were 10% faster in HCM myocytes. Myofibrillar Ca2+ sensitivity in HCM myocytes (pCa50 = 6.40 ± 0.05) was higher than for donor myocytes (pCa50 = 6.09 ± 0.02; P < 0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca2+ concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca2+-activated force and high Ca2+ sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients.
Research Highlights
► The passive stiffness of skinned HCM cardiac myocytes was similar to that of normal (donor) myocytes. ► Maximum Ca-activated force production was reduced by 40% in HCM vs donor myocytes. ► This loss of force could contribute to systolic dysfunction in HCM hearts. ► Myofibrillar Ca sensitivity was higher in HCM than in donor myocytes. ► The enhanced Ca sensitivity could compensate for the smaller maximum force but would tend to cause diastolic dysfunction. ► These characteristics were common to all HCM patients studied, suggesting the changes were secondary consequence of the underlying genetic variants.
doi:10.1016/j.yjmcc.2010.06.006
PMCID: PMC2954357  PMID: 20615414
Hypertrophic cardiomyopathy; Skinned cardiac myocytes; Viscoelasticity; Ca2+ sensitivity; Cross-bridge kinetics
23.  TNNI3K, a Cardiac-Specific Kinase, Promotes Physiological Cardiac Hypertrophy in Transgenic Mice 
PLoS ONE  2013;8(3):e58570.
Purpose
Protein kinase plays an essential role in controlling cardiac growth and hypertrophic remodeling. The cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific kinase, is associated with cardiomyocyte hypertrophy. However, the precise function of TNNI3K in regulating cardiac remodeling has remained controversial.
Methods and Results
In a rat model of cardiac hypertrophy generated by transverse aortic constriction, myocardial TNNI3K expression was significantly increased by 1.62 folds (P<0.05) after constriction for 15 days. To investigate the role of TNNI3K in cardiac hypertrophy, we generated transgenic mouse lines with overexpression of human TNNI3K specifically in the heart. At the age of 3 months, the high-copy-number TNNI3K transgenic mice demonstrated a phenotype of concentric hypertrophy with increased heart weight normalized to body weight (1.31 fold, P<0.01). Echocardiography and non-invasive hemodynamic assessments showed enhanced cardiac function. No necrosis or myocyte disarray was observed in the heart of TNNI3K transgenic mice. This concentric hypertrophy maintained up to 12 months of age without cardiac dysfunction. The phospho amino acid analysis revealed that TNNI3K is a protein-tyrosine kinase. The yeast two-hybrid screen and co-immunoprecipitation assay identified cTnI as a target for TNNI3K. Moreover, TNNI3K overexpression induced cTnI phosphorylation at Ser22/Ser23 in vivo and in vitro, suggesting that TNNI3K is a novel upstream regulator for cTnI phosphorylation.
Conclusion
TNNI3K promotes a concentric hypertrophy with enhancement of cardiac function via regulating the phosphorylation of cTnI. TNNI3K could be a potential therapeutic target for preventing from heart failure.
doi:10.1371/journal.pone.0058570
PMCID: PMC3589374  PMID: 23472207
24.  Use of a highly-sensitive cardiac troponin I assay in a screening population for hypertrophic cardiomyopathy: a case-referent study 
Background
Hypertrophic cardiomyopathy (HCM) is a genetic condition, and relatives of affected persons may be at risk. Cardiac troponin biomarkers have previously been shown to be elevated in HCM. This study examines the new highly-sensitive cardiac troponin I (hsTnI) assay in a HCM screening population.
Methods
Nested case–control study of consecutive HCM sufferers and their relatives recruited from May 2010 to September 2011. After informed consent, participants provided venous blood samples and clinical and echocardiographic features were recorded. Associations between the natural log (ln) of the contemporary troponin I (cTnI) and hsTnI assays and markers of cardiac hypertrophy were examined. Multiple regression models were fitted to examine the predictive ability of hsTnI for borderline or definite HCM.
Results
Of 107 patients, 24 had borderline and 19 had definite changes of HCM. Both TnI assays showed significant, positive correlations with measures of cardiac muscle mass. After age and sex adjustment, the area under the receiver operator characteristic (AUROC) curve for the outcome of HCM was 0.78, 95% CI [0.65, 0.90], for ln(hsTnI), and 0.66, 95% CI [0.51, 0.82], for ln(cTnI) (p=0.11). Including the hsTnI assay in a multiple-adjusted “screening” model for HCM resulted in a non-significant improvement in both the AUROC and integrated discrimination index.
Conclusions
Both cTnI and hsTnI show a graded, positive association with measures of cardiac muscle mass in persons at risk of HCM. Further studies will be required to evaluate the utility of these assays in ECG- and symptom-based identification of HCM in at-risk families.
doi:10.1186/1471-2261-13-70
PMCID: PMC3849957  PMID: 24020864
Hypertrophic cardiomyopathy; High-risk screening; Troponin I; Biomarkers; Highly-sensitive assays
25.  On Genetic and Phenotypic Variability of Hypertrophic Cardiomyopathy: Nature Versus Nurture* 
The seminal discovery of the R403Q mutation in the beta-myosin heavy chain (MyHC) gene as a cause of hypertrophic cardiomyopathy (HCM) by Dr. Thierfelder’s group a decade ago (1) ushered in a new era in the molecular genetics of HCM. To date, over 120 mutations in 10 genes, all encoding sarcomeric proteins, have been identified in patients with HCM (2), leading to the notion that HCM is a disease of contractile sarcomeric proteins (3). Mutations in nonsarcomeric genes, mitochondrial genome and genes responsible for the triplet repeat syndromes also have been found in patients with HCM (2). Although no large-scale systematic search has yet been performed, the existing data suggest that mutations in the beta-MyHC, myosin binding protein-C (MyBP-C) and cardiac troponin T (cTnT) are the most common causes of HCM, collectively accounting for approximately 60% to 70% of all HCM cases (2). It has also become evident that the frequency of each particular causal mutation in the HCM population is relatively low (<5%). Overall, genetic studies indicate significant allelic and nonallelic heterogeneity of HCM, an issue that complicates the feasibility of genetic diagnosis.
PMCID: PMC2900847  PMID: 11499720

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