Sarcomere Protein Genes Research Articles

Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene

Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candidate gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chinese girl with restrictive cardiomyopathy. This study indicates that mutation in sarcomere protein genes may play an important role in idiopathic pediatric restrictive cardiomyopathy.

Fast Diastolic Swinging Motion of the Mitral Valve as a Clinical Marker of Familial Hypertrophic Cardiomyopathy in Genetically Affected Young Children without Left Ventricular Hypertrophy: A New Role for Noninvasive Imaging?

Structural mitral valve (MV) abnormalities are common in patients with hypertrophic cardiomyopathy (HCM). This is the first report demonstrating MV abnormalities in very young children as the sole overt clinical feature of a known HCM-causing sarcomere protein gene mutation. Due to MV leaflet elongation, we also noticed a typical fast diastolic swinging motion of the MV in our patients. This novel echocardiographic feature may be used as a clinical marker of HCM disease in the absence of left ventricular hypertrophy.

Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing

BackgroundClinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of...

Clinical Implication of Genetic Testing for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is caused by a dominant mutation of the sarcomere protein gene in approximately 60% of cases. Genetic testing of HCM has several benefits. Diagnosis can be confirmed if the sarcomere protein gene mutation is identified. Genetic testing enables to follow-up blood relatives who are mutationpositive only, and can identify asymptomatic and non-onset patients. Relatives with negative results of genetic testing could be freed from anguish. On the other hand, genetic testing has some disadvantages. Treatment often does not change after testing. Forty percent of cases has unknown causative genes. Relationship between gene mutation and clinical findings or treatment responsiveness is little known, and so on. Many issues need to be resolved to incorporate genetic diagnosis into daily practice for HCM. However, genetic testing for HCM cannot be regarded as unnecessary and expensive debauchery, but rather represents a valuable measure in the medical facilities. Although there still remain questions about genetic diagnosis of HCM, accumulated knowledge to date is fairly enough to establish the genetic testing as a useful tool for individualized management of HCM patients and their families.

Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3. The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.

Toronto Hypertrophic Cardiomyopathy Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy

Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype. Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (-1), 30 to 39 (-2), 40 to 49 (-3), 50 to 59 (-4), 60 to 69 (-5), 70 to 79 (-6), ≥80 (-7); female sex (4); arterial hypertension (-4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer-Lemeshow goodness-of-fit P=0.22. The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.

Hypertrophic cardiomyopathy: Translating cellular cross talk into therapeutics

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with serious adverse outcomes, including heart failure, arrhythmias, and sudden cardiac death. The discovery that mutations in sarcomere protein genes cause HCM has enabled the development of mouse models that recapitulate clinical manifestations of disease. Studies in these models have provided unexpected insights into the biophysical and biochemical properties of mutated contractile proteins and may help to improve clinical diagnosis and management of patients with HCM.

Sudden Cardiac Death in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common disorder of cardiac muscle associated with sudden cardiac death (SCD). HCM is defined by increased left ventricular wall thickness or mass, in the absence of abnormal loading conditions to account for the observed abnormality.1 In most adults, the disease is inherited as an autosomal dominant trait and is caused by mutations in cardiac sarcomere protein genes.1 Histologically, HCM is characterized by myocardial disarray, fibrosis, and small vessel disease.2 Macroscopically, the hypertrophy is typically asymmetrical and 25% of patients have resting left ventricular outflow tract obstruction (LVOTO).3 SCD in HCM is caused mainly by ventricular arrhythmias that can be effectively treated by implantable cardioverter defibrillator (ICD) therapy. Identification of patients at high risk is a cornerstone of management and research during the past 4 decades has recognized a number of phenotypic characteristics that can be used to identify those patients who might benefit from an ICD. ### Genetics and Pathogenesis In infants and children, HCM is often associated with syndromes (eg Noonan’s syndrome, LEOPARD syndrome) and metabolic diseases (eg, glycogen storage diseases).1 In adults and adolescents, HCM is primarily caused by mutations in cardiac sarcomeric protein genes, and is inherited in an autosomal dominant manner.1 Mutations in these genes can be found in ≈60% of patients, and MYBPC3 and MYH7 mutations account for the majority of cases. Genotype–phenotype correlations are weak, with significant interfamily and intrafamily phenotypic variability. Exactly how HCM develops as a consequence of sarcomere protein gene mutations is not known.4 ### Sudden Cardiac Death and Underlying Mechanisms Existing data indicate that most patients with HCM die from cardiac causes,5–7 but this may reflect referral bias from centers reporting on mortality in HCM. Although the data do not exist, based on prevalence of 1/500,8 it is likely that most patients with HCM remain …

Distal arthrogryposis: clinical and genetic findings

Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation. We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed. A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection. The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.

Prevalence of Sequence Variants in the RAS-Mitogen Activated Protein Kinase Signaling Pathway in Pre-Adolescent Children With Hypertrophic Cardiomyopathy

Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.

Exploration par le système ISAC des manifestations d’allergie alimentaire aux aliments végétaux chez l’adulte

Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder caused by mutationally altered dominant-acting sarcomere proteins, exhibits significant clinical heterogeneity. To determine whether genetic background could influence the expression of this disease, we studied a murine model for this human condition. Hypertrophic responses to the Arg403Gln missense mutation in a cardiac myosin heavy chain gene were compared in 129SvEv (inbred; designated 129SvEv-α MHC403/+) and Black Swiss (outbred; designated BSw- α MHC403/+) strains. At 30–50 weeks of age all 129SvEv- α MHC403/+showed left ventricular hypertrophy, while left ventricular wall thickness was increased in only half of BSw- α MHC403/+mice demonstrating that a polymorphic modifier gene can determine the hypertrophic response to this dominant-acting sarcomere protein mutation. Further analysis suggests that SJL/J mice bear a recessive allele of this modifier gene that prevents a hypertrophic response to the Arg403Gln missense mutation. We conclude that genetic modifiers in mice, and presumably in man, can alter the hypertrophic response to sarcomere protein gene missense mutations.

Appropriate implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: What happens on Sunday afternoons in May?

This editorial refers to ‘The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy’ by C. O'Mahony et al ., on page 724 Hypertrophic cardiomyopathy (HCM) is a clinically and genetically heterogeneous disease. Sudden cardiac death (SCD) is the most devastating complication of HCM. The substrate for potentially life-threatening ventricular arrhythmias (VA) in HCM is complex. The hypertrophy causes dispersion of repolarization and refractoriness, which increases the vulnerability to triggered arrhythmia. Myocardial disarray, the histological hallmark of the disease leads to a disruption of cell-to-cell alignment and together with the expansion of the interstitial compartment and replacement fibrosis creates unidirectional conduction block that predispose to re-entry arrhythmia. Sarcomeric protein gene mutations influence calcium homeostasis, and abnormalities in ion fluxes during repolarization can cause after-depolarization and triggered activity. This unpredictable, complex arrhythmogenic substrate is further influenced by maladaptive autonomic responses, myocardial ischaemia, left ventricular outflow tract obstruction, and currently unknown factors.1 Although these characteristics are to some extent present in most HCM patients, risk of SCD in the general HCM population is low.2 The risk of sudden death increases in the presence of the following clinical risk factors: positive family history of SCD, unexplained syncope, abnormal blood pressure response to exercise, left ventricular wall thickness ≥30 mm, …

Prevalence and Distribution of Sarcomeric Gene Mutations in Japanese Patients With Familial Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese. Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations. This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan.

Myocardial contractile and metabolic properties of familial hypertrophic cardiomyopathy caused by cardiac troponin I gene mutations: a simulation study

Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is caused by sarcomeric protein gene mutations. The mechanism by which these mutant proteins cause disease is uncertain. Experimentally, cardiac troponin I (CTnI) gene mutations mainly alter myocardial performance via increases in the Ca(2+) sensitivity of cardiac contractility. In this study, we used an integrated simulation that links electrophysiology, contractile activity and energy metabolism of the myocardium to investigate alterations in myocardial contractile function and energy metabolism regulation as a result of increased Ca(2+) sensitivity in CTnI mutations. Simulation results reproduced the following typical features of FHC: (1) slower relaxation (diastolic dysfunction) caused by prolonged [Ca(2+)](i) and force transients; (2) higher energy consumption with the increase in Ca(2+) sensitivity; and (3) reduced fatty acid oxidation and enhanced glucose utilization in hypertrophied heart metabolism. Furthermore, the simulation indicated that in conditions of high energy consumption (that is, more than an 18.3% increase in total energy consumption), the myocardial energetic metabolic network switched from a net consumer to a net producer of lactate, resulting in a low coupling of glucose oxidation to glycolysis, which is a common feature of hypertrophied hearts. This study provides a novel systematic myocardial contractile and metabolic analysis to help elucidate the pathogenesis of FHC and suggests that the alterations in resting heart energy supply and demand could contribute to disease progression.

Analysis of the sarcomere protein gene mutation on cardiomyopathy—Mutations in the troponin complex genes

Developments in the molecular genetic studies of cardiomyopathy (CM) have led to discovery of a large number of mutations in the genes encoding the sarcomeric proteins. In this study, comprehensive screening of TNNT2, TNNI3 and TNNC1 was performed in 36 consented autopsy cases diagnosed as CM, in order to evaluate the prevalence of gene mutations in sudden death caused by CM. A total of 12 mutations and 15 single nucleotide polymorphisms (SNPs) were detected. It was indicated that this study contribute to genetic based diagnosis, risk stratification and prevention of sudden death caused by CM.

Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6

BackgroundSox6 is a multi-faceted transcription factor involved in the terminal differentiation of many different cell types in vertebrates. It has been suggested that in mice as well as in zebrafish Sox6 plays a role in the terminal differentiation of skeletal muscle by suppressing transcription of slow fiber specific genes. In order to understand how Sox6 coordinately regulates the transcription of multiple fiber type specific genes during muscle development, we have performed ChIP-seq analyses to identify Sox6 target genes in mouse fetal myotubes and generated muscle-specific Sox6 knockout (KO) mice to determine the Sox6 null muscle phenotype in adult mice.ResultsWe have identified 1,066 Sox6 binding sites using mouse fetal myotubes. The Sox6 binding sites were found to be associated with slow fiber-specific, cardiac, and embryonic isoform genes that are expressed in the sarcomere as well as transcription factor genes known to play roles in muscle development. The concurrently performed RNA polymerase II (Pol II) ChIP-seq analysis revealed that 84% of the Sox6 peak-associated genes exhibited little to no binding of Pol II, suggesting that the majority of the Sox6 target genes are transcriptionally inactive. These results indicate that Sox6 directly regulates terminal differentiation of muscle by affecting the expression of sarcomere protein genes as well as indirectly through influencing the expression of transcription factors relevant to muscle development. Gene expression profiling of Sox6 KO skeletal and cardiac muscle revealed a significant increase in the expression of the genes associated with Sox6 binding. In the absence of the Sox6 gene, there was dramatic upregulation of slow fiber-specific, cardiac, and embryonic isoform gene expression in Sox6 KO skeletal muscle and fetal isoform gene expression in Sox6 KO cardiac muscle, thus confirming the role Sox6 plays as a transcriptional suppressor in muscle development.ConclusionsOur present data indicate that during development, Sox6 functions as a transcriptional suppressor of fiber type-specific and developmental isoform genes to promote functional specification of muscle which is critical for optimum muscle performance and health.

Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress.

134 Mutations in the sarcomere protein gene MYH7 in Ebstein's anomaly

Background Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. As there have been reports of abnormal left ventricular morphology and function in patients with Ebstein's anomaly we hypothesised that mutations in the β-myosin heavy chain (MYH7) may be associated with Ebstein's anomaly. Methods MYH7 mutation analysis was undertaken in 141 unrelated affected individuals with Ebstein's anomaly using next-generation sequencing on the 454 platform. 64 probands had no associated cardiac anomalies. The most common associated cardiac malformation were atrial septal defect (48 probands) and left ventricular non-compaction (LVNC) (7 probands). Where mutations were discovered, family studies were undertaken and the segregation of the mutation with disease was investigated. Results Heterozygous mutations were identified in eight of the probands including six of the seven with LVNC. Two patients had the same mutation; of the seven distinct mutations, five were novel (four missense changes and an in-frame deletion) and two have been previously reported in patients with hypertrophic cardiomyopathy. Family studies revealed additional members with LVNC for three of the probands, one of whom also had a relative with Ebstein's anomaly. In these three pedigrees the mutation segregated with disease. Conclusions Mutations in MYH7 occur relatively frequently in Ebstein's anomaly accompanied by LVNC. This study is another example of mutations in a sarcomere protein causing congenital heart malformation.

Ebstein’s anomaly may be caused by mutations in the sarcomere protein gene MYH7

Ebstein’s anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein’s anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein’s anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein’s anomaly and LVNC and its implications for the clinical care for patients and their family members.

Sarcomere Protein Gene Mutations in Patients With Apical Hypertrophic Cardiomyopathy

Apical hypertrophic cardiomyopathy (HCM) is a unique form of HCM with left ventricular hypertrophy confined to the cardiac apex. The purpose of our study was to report genetic findings in a large series of unrelated patients with apical HCM and compare them with a nonapical HCM cohort. Overall, 429 patients with HCM underwent genetic testing. The panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2). Sixty-one patients were diagnosed with apical HCM. A positive genotype was found in 8 patients with apical HCM. The genotype-positive and genotype-negative patients had similar maximal wall thicknesses (17.5 ± 3.5 mm versus 17.6 ± 3.3 mm, P = 0.71) and similar frequency of HCM-related events (2/8; 25% versus 13/53; 25%; P = 0.98). Thirteen percent with apical HCM and 40% with nonapical HCM had a positive genotype (P<0.001) most often involving the MYBPC3 and MYH7 genes. In apical HCM, a positive genotype was found less frequently than in nonapical HCM, and it was most often involving MYBPC3 and MYH7 genes. Only 13% of patients with apical HCM were found to be genotype positive, indicating that genome-wide association studies and gene expression profiling are needed for better understanding of the genetic background of the disease. There was no significant genotype-phenotype correlation in our cohort with apical HCM.