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PubMed2005

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia.

Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.

Animals↗
PubMed1999

Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation.

OBJECTIVE: To investigate changes in the alignment of the sarcomeric filaments in hypertrophic cardiomyopathy and the effects of cardiac beta myosin heavy chain (beta-MHC) mutation on the sarcomeric ultrastructure. DESIGN: A retrospective analysis. PATIENTS: Endomyocardial biopsy samples were examined by transmission electron microscopy in seven patients with hypertrophic cardiomyopathy and beta-MHC mutation, six with hypertrophic cardiomyopathy but without the mutation, and five controls (with chest pain syndromes). MAIN OUTCOME MEASURE: Alignment of the sarcomeric filaments and the distance between neighbouring thick myosin filaments. RESULTS: In controls, cross sections of the sarcomere at the A band showed a highly organised orthohexagonal array with 6 thin actin filaments surrounding one thick myosin filament, whereas in hypertrophic cardiomyopathy the alignment of the sarcomeric filaments was sparse and disrupted. In hypertrophic cardiomyopathy with a mutation, the distance between neighbouring thick myosin filaments was greater than in controls (mean (SD) 45.3 (4.7) v 38.5 (3.5) nm, p < 0.05), and the variance of the distance was greater than in controls (8.0 (0.7) v 4.8 (1.0) nm, p < 0.001) or in patients with hypertrophic cardiomyopathy without a mutation (6.7 (0.6) nm, p < 0.05). In the latter, the variance of the distance was also greater than in the controls (p < 0.01). A significant correlation was found between the grade of the myocyte hypertrophy and the variance of the distance (r = 0.654; p < 0.01). CONCLUSIONS: The alignment of the sarcomeric filaments is disrupted in hypertrophic cardiomyopathy, particularly when there is beta-MHC mutation.

Adolescent↗
PubMed2001

Early and selective disappearance of telethonin protein from the sarcomere in neurogenic atrophy.

Mutations of the human telethonin gene have recently been shown to cause limb girdle muscular dystrophy type 2G in three Brazilian families. The mRNA has been shown to be dynamically regulated in animals, however, the fate of the protein in human muscle is unknown. In order to assess the expression of telethonin in more frequently encountered myopathological conditions we generated and characterized a rabbit antiserum raised against the C-terminal end of telethonin by immunoblotting and immunogold EM. Indirect immunofluorescence analysis of a wide variety of neuromuscular disorders including dystrophinopathies, metabolic myopathies, denervation disorders, congenital and inflammatory myopathies revealed that the characteristic Z-band staining of telethonin was preserved in all disease entities included in our study. However, a reduced telethonin immunoreactivity was observed in up to 10% of type II fibers in 10 cases of neurogenic atrophy. A decreased telethonin staining was more frequently observed in early stages of fiber atrophy than in type II fibers displaying normal or highly atrophic fiber diameters. Hence, not only the telethonin transcript is rapidly downregulated in denervated muscle but the protein itself undergoes dynamic changes while its known sarcomeric binding partner titin remains unaltered. Beyond its role as a static component of Z-bands, these findings indicate that telethonin protein levels seems to be at least in part regulated by neuronal activity and is thus linked to the dynamic control of myofibrillogenesis and muscle turnover in human skeletal muscle.

Blotting, Western↗
PubMed2004

Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.

Adult↗
PubMed2001

Molecular genetics and pathogenesis of hypertrophic cardiomyopathy.

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 gamma 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 beta-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.

Animals↗
PubMed2006

Mutation screening of the PTPN11 gene in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden death. It is an autosomal dominant disorder predominantly caused by mutations in genes encoding for sarcomeric proteins. Only 50-60% of HCM probands have mutations in known genes suggesting the presence of additional disease genes. Noonan and LEOPARD syndromes are characterised by multiple dysmorphia and cardiac defects with HCM present in approximately 20% of cases. Both syndromes are caused by mutations in the PTPN11 gene which codes for the protein tyrosine phosphatase SHP-2. It is suspected but unproven that the cardiac phenotype may predominate or even be present in isolation. In order to determine possible involvement of this gene in the pathogenesis of HCM, we performed mutation screening of the PTPN11 coding region in 250 selected HCM probands (200 patients without mutations in sarcomeric genes and 50 with identified mutations). No mutations in PTPN11 were identified. Our data suggests that mutations in the PTPN11 gene are not a cause of HCM in the absence of Noonan/LEOPARD syndromes.

Adult↗
PubMed2006

Novel mitochondrial DNA mutations implicated in Noonan syndrome.

We report a case of Noonan syndrome with compound mutations in a sarcomeric contractile protein gene and several novel mutations in mitochondrial genes. Our case forms the first report, which emphasizes the importance of mtDNA mutations in Noonan syndrome and extends the scope for mitochondrial related syndromes.

Carrier Proteins↗
PubMed2006

Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype. METHODS: The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed. RESULTS: The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated. CONCLUSION: The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

Adolescent↗
PubMed2003

Familial hypertrophic cardiomyopathy mutations in troponin I (K183D, G203S, K206Q) enhance filament sliding.

A major cause of familial hypertrophic cardiomyopathy (FHC) is dominant mutations in cardiac sarcomeric genes. Linkage studies identified FHC-related mutations in the COOH terminus of cardiac troponin I (cTnI), a region with unknown function in Ca(2+) regulation of the heart. Using in vitro assays with recombinant rat troponin subunits, we tested the hypothesis that mutations K183Delta, G203S, and K206Q in cTnI affect Ca(2+) regulation. All three mutants enhanced Ca(2+) sensitivity and maximum speed (s(max)) of filament sliding of in vitro motility assays. Enhanced s(max) (pCa 5) was observed with rabbit skeletal and rat cardiac (alpha-MHC or beta-MHC) heavy meromyosin (HMM). We developed a passive exchange method for replacing endogenous cTn in permeabilized rat cardiac trabeculae. Ca(2+) sensitivity and maximum isometric force did not differ between preparations exchanged with cTn(cTnI,K206Q) or wild-type cTn. In both trabeculae and motility assays, there was no loss of inhibition at pCa 9. These results are consistent with COOH terminus of TnI modulating actomyosin kinetics during unloaded sliding, but not during isometric force generation, and implicate enhanced cross-bridge cycling in the cTnI-related pathway(s) to hypertrophy.

Actin Cytoskeleton↗
PubMed2000

Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.

Amino Acid Sequence↗
PubMed2000

An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy.

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)), when treated with calcineurin inhibitors or a K(+)-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca(2+) concentrations in wild-type cardiac myocytes; alphaMHC(403/+) myocytes failed to respond. Pretreatment with a Ca(2+)-channel antagonist abrogated diastolic Ca(2+) changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alphaMHC(403/+) mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca(2+) responses that initiate a hypertrophic response. These data define an important Ca(2+)-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Animals↗
PubMed2005

Protein aggregate myopathies.

Protein aggregate myopathies (PAM) are an emerging group of muscle diseases characterized by structural abnormalities. Protein aggregate myopathies are marked by the aggregation of intrinsic proteins within muscle fibers and fall into four major groups or conditions: (1) desmin-related myopathies (DRM) that include desminopathies, a-B crystallinopathies, selenoproteinopathies caused by mutations in the, a-B crystallin and selenoprotein N1 genes, (2) hereditary inclusion body myopathies, several of which have been linked to different chromosomal gene loci, but with as yet unidentified protein product, (3) actinopathies marked by mutations in the sarcomeric ACTA1 gene, and (4) myosinopathy marked by a mutation in the MYH-7 gene. While PAM forms 1 and 2 are probably based on impaired extralysosomal protein degradation, resulting in the accumulation of numerous and diverse proteins (in familial types in addition to respective mutant proteins), PAM forms 3 and 4 may represent anabolic or developmental defects because of preservation of sarcomeres outside of the actin and myosin aggregates and dearth or absence of other proteins in these actin or myosin aggregates, respectively. The pathogenetic principles governing protein aggregation within muscle fibers and subsequent structural sarcomeres are still largely unknown in both the putative catabolic and anabolic forms of PAM. Presence of inclusions and their protein composition in other congenital myopathies such as reducing bodies, cylindrical spirals, tubular aggregates and others await clarification. The hitherto described PAMs were first identified by immunohistochemistry of proteins and subsequently by molecular analysis of their genes.

Actins↗
PubMed2006

Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene.

BACKGROUND: Idiopathic (primary) hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in genes encoding sarcomeric proteins. One of the most commonly mutated HCM genes is the myosin binding protein C (MYBPC3) gene. Mutations in this gene lead mainly to truncation of the protein which gives rise to a relatively mild phenotype. Pure HCM in neonates is rare and most of the time childhood HCM occurs in association with another underlying condition. OBJECTIVE: To study the presence of mutations in the MYBPC3 gene in idiopathic childhood HCM. METHODS: MYBPC3 coding region and splice junction variation were analysed by denaturing high performance liquid chromatography (DHPLC) and sequencing in DNA isolated from two neonates with severe unexplained HCM, who died within the first weeks of life. RESULTS: Truncating mutations were found in both alleles of the MYBPC3 gene in both patients, suggesting there was no functional copy of the MYBPC3 protein. Patient 1 carried the maternally inherited c.2373_2374insG mutation and the paternally inherited splice-donor site mutation c.1624+1G-->A. Patient 2 carried the maternally inherited frameshift mutation c.3288delA (p.Glu1096fsX92) and the paternally inherited non-sense mutation c.2827C-->T (p.Arg943X). CONCLUSIONS: The findings indicate the need for mutation analysis of genes encoding sarcomeric proteins in childhood HCM and the possibility of compound heterozygosity.

Cardiomyopathy, Hypertrophic↗
PubMed1999

Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.

We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between -2.5 and -6.0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC is the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.

Actins↗
PubMed2003

[Hypertrophic cardiomyopathies].

Hypertrophic cardiomyopathy (CMH) is characterised by hypertrophy of the left ventricle, typically predominantly asymmetric on the interventricular septum. The dreaded complication of the disease is sudden death, especially on physical exertion, and this can constitute the first symptom of the disease. Classified as primary or idiopathic for a long time, there have been considerable recent advances in the molecular genetics which have allowed the physiopathology of the disease to be unveiled. There is great genetic heterogeneity but the different genes have in common a coding for sarcomere proteins. Functional studies suggest that the mutations entail a primary alteration of sarcomere function, with secondary and compensatory hypertrophy. The genetic data equally offer the opportunity to re-evaluate the natural history and the clinical spectrum of the disease. A better understanding of the disease, coming from these molecular data, has allowed a great improvement in the relevance of the information given to patients and their relatives during genetic counselling consultations. The performance of a genetic test with a medical aim can equally be discussed in certain specific situations.

Cardiomyopathy, Hypertrophic↗
PubMed2002

Transgenic rabbits expressing mutant essential light chain do not develop hypertrophic cardiomyopathy.

Mutations in multiple sarcomeric proteins can cause familial hypertrophic cardiomyopathy. Although a M149V mutation in the myosin light chain is associated with the human disease, the data from transgenic (TG) mouse models are conflicting. When a human genomic fragment containing the M149V essential myosin light chain was used to generate TG mice, the phenotype was recapitulated. However, when the mouse cDNA containing the mutation was used to generate TG animals, no phenotype could be discerned. TG rabbits can be a valuable complement and extension to mouse-based TG models and we wished to determine whether expression of this mutation in the rabbit heart would result in the disease. The rabbit essential light chain cDNA was isolated, sequenced, the M149V mutation made and the cDNA placed into the beta-myosin heavy chain promoter, which efficiently drives cardiac expression in the rabbit ventricles. Multiple TG rabbit lines showing different levels of protein replacement were obtained. No discernible pattern of disease was apparent at the structural or functional levels at either the neonatal, juvenile or adult stages. We conclude that the M149V mutation is not causative for FHC when expressed in the rabbit within the context of the endogenous protein.

Amino Acid Substitution↗
PubMed2026

Genetic diversity and molecular mechanisms in hypertrophic cardiomyopathy: toward personalized therapy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-&#x3b2; (TGF-&#x3b2;) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.

Humans↗
PubMed2005

One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region.

Familial hypertrophic cardiomyopathy (FHC) is, in most cases, a disease of the sarcomere, caused by a mutation in one of 10 known sarcomere disease genes. More than 266 mutations have been identified since 1989. The FHC disease gene first characterized MYH7, encodes the cardiac beta-myosin heavy chain, and contains more than 115 of these mutations. However, in most studies, only the region encoding the globular head and the hinge region of the mature cardiac beta-myosin heavy chain have been investigated. Furthermore, most studies carries out screening for mutations in the most prevalent disease genes, and discontinues screening when an apparent disease-associated mutation has been identified. The aim of the present study was to screen for mutations in the rod region of the MYH7 gene in all probands of the cohort, regardless of the known genetic status of the proband. Three disease-causing mutations were identified in the rod region in four probands using capillary electrophoresis single-strand conformation polymorphism as a screening method. All mutations were novel: N1327K, R1712W, and E1753K. Two of the probands had already been shown to carry other FHC-associated mutations. In conclusion, we show that in the Danish cohort we find one third of all MYH7 mutations in the rod-encoding region and we find that two of the patients carrying these mutations also carry mutations in other FHC disease genes stressing the need for a complete screening of all known disease genes in FHC-patients.

Amino Acid Substitution↗