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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac contraction is triggered by the cyclic interaction of the "molecular motor" protein myosin with the actin filament, consuming ATP as the energy source to produce tension or shortening. The myosin heavy chain (MHC) contains the actin- and ATP-binding sites and represents the molecular motor of muscle contraction. This review describes the various subunits of human heart myosin in health and disease and discusses their functions. Two different MHC genes (alpha and beta) with distinct biochemical features are expressed in the human heart. Alpha-MHC confers a higher ATPase activity and higher shortening velocity to the heart than beta-MHC. Motor function is regulated by myosin light chain (MLC) isoforms. Expression of the atrial MLC-1 isoform in the hypertrophied human ventricle increases cross-bridge cycling and contractility. It is suggested that MLC-1 acts as a MHC/actin tether. Weakening of this tether increases myosin function. MLC-2 slows the rate of tension development of myosin. This relative inhibition is relieved upon phosphorylation of the MLC-2 perhaps caused by "swing-out" of cross-bridges from the myosin filament. Mutations in all ventricular myosin subunits have been found in patients with hypertrophic cardiomyopathy.
J Mol Med (Berl) 1999 Jul
PMID:Tuning the human heart molecular motors by myosin light chains. 1049

The adult rodent heart adapts to increased work load by reexpression of its fetal genes, for example, beta-myosin heavy chain (MHC), in order to improve contractile function. However, the human ventricle regulates contractility by expression of atrial essential myosin light chain (ALC-1) rather than beta-MHC. We evaluated the impact of both mechanisms in patients with hypertrophic cardiomyopathy. MHC isoform expression was quantified at the mRNA and protein levels by reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Although alpha-MHC mRNA was detected in control and hypertrophied human ventricular tissue, alpha-MHC protein was not observed. Similarly, we investigated the expression of ALC-1 by two-dimensional polyacrylamide gel electrophoresis and the clinical and hemodynamic parameters of the patients with hypertrophic cardiomyopathy. We found a significant positive correlation between ALC-1 protein expression and dP/dtmax in the hypertrophied human ventricle in vivo. Correlations between dP/dtmax and expression of protein for the ryanodine receptor and L-type Ca2+ channel were excluded. Our data suggest that reexpression of ALC-1 improves the contractile state of the adult human heart. We propose that two evolutionarily divergent compensatory mechanisms for increased work demand exist in the mammalian heart: MHC regulation in rodents and essential MLC regulation, of cardiac contractility, in humans.
J Mol Med (Berl) 1999 Sep
PMID:Expression of atrial myosin light chains but not alpha-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy. 1056

Defects in seven genes encoding sarcomere proteins have been shown to cause hypertrophic cardiomyopathy. To date, only one study reporting defects in the cardiac troponin I gene associated with hypertrophic cardiomyopathy has been published, and the proportion of hypertrophic cardiomyopathy cases caused by defects in this gene is unknown. Therefore, the authors screened 37 unrelated Finnish patients with hypertrophic cardiomyopathy for variants in the cardiac troponin I gene. Exons 1-8 of the troponin I gene were screened with the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. Five different variants (four intron variants and one silent exon variant) were found. Most variants were also present in control samples and none of the variants co-segregated with the disease in families. The results of the present study indicate that defects in the cardiac troponin I gene do not cause hypertrophic cardiomyopathy in patients from Eastern Finland.
J Mol Cell Cardiol 1999 Nov
PMID:The cardiac troponin I gene is not associated with hypertrophic cardiomyopathy in patients from eastern Finland. 1059 Oct 29

Mutations in human cardiac myosin-binding protein C (cMyBP-C) gene are associated with familial hypertrophic cardiomyopathy (FHC), and most of them are predicted to produce COOH-truncated proteins. To understand the molecular mechanism(s) by which such mutations cause FHC, we analyzed (i) the accumulation of human cMyBP-C mutants in fetal rat cardiomyocytes, and (ii) the protein sequence of the human wild-type (wt) cMyBP-C by hydrophobic cluster analysis with the aim of identifying new putative myosin-binding site(s). Accumulation and sarcomeric localization of the wt protein and of four FHC-mutant cMyBP-Cs (E542Q and three COOH-truncated proteins) were studied in cardiomyocytes by immunostaining and confocal microscopy after transfection with myc-tagged constructs. We found that: (i) 10 % of the cells expressing COOH-truncated mutants exhibit an incorporation into the A-band of the sarcomere without any alteration of the myofibrillar architecture versus 76 % of those expressing the wt or E542Q mutant cMyBP-Cs (p<0.001); (ii) 90 % of the cells expressing the truncated mutants show a diffuse localization of these proteins in the cardiomyocytes, out of which 45 % exhibit a significant alteration of the sarcomeric structure (p<0.0001 versus wt); and (iii) the two shortest mutant cMyBP-Cs accumulate at very low levels in fetal rat cardiomyocytes as compared to the wt (p<0.008). Protein sequence analysis indicated that a 45-residue sequence in the NH2-terminal C0 domain of cMyBP-C exhibits a consistent homology (sequence similarity score of 42 %) with a segment of the NH2-terminal domain of myomesin, another myosin-binding protein. This result suggests that the C0 domain of human cMyBP-C contains a novel putative myosin-binding site that could account for the A-band incorporation of the truncated mutants. In addition, the faint accumulation and the diffuse localization of truncated mutants could probably be explained by a low affinity of the C0 domain for myosin. We conclude that COOH-truncated cMyBP-Cs may act as poison polypeptides that disrupt the myofibrillar architecture and result in the defects observed in FHC.
J Mol Biol 1999 Nov 26
PMID:COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. 1061 Jul 70

The causality of mutant sarcomeric proteins in hypertrophic cardiomyopathy (HCM) is well established. The current emphasis is to elucidate the pathogenesis of HCM in transgenic animal models. We determined the left ventricular ejection fraction (LVEF) in transgenic mice expressing mutant cardiac troponin T (cTnT)-Q(92), known to cause HCM in humans. Transgenes were constructed by placing wild-type (R(92)) or mutant (Q(92)) full-length human cTnT cDNAs 3' into a 5.5-kb murine [alpha -myosin heavy chain (MyHC)] promoter injected into fertilized zygotes. Three wild-type and six mutant lines were produced. Transgene mRNA and proteins, detected using transgene-specific probes were expressed at high levels in all wild-type and three mutant lines. The total cTnT mRNA pool was increased by up to five-fold in transgenic mice, but the total cTnT protein remained unchanged. The mean values of LVEF, determined by(178)Ta radionuclide angiography, were 57.8+/-6% (n=4) in non-transgenic littermate (NLM), 53.3+/-10 (n=6) in wild-type and 39. 4+/-6 (n=5) in mutant transgenic mice (P=0.009). The heart/body weight ratios and the number of cells stained with terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling were similar among the groups. Three mutant mice had myocyte disarray and excess interstitial collagen and two had normal myocardial structure despite having reduced LVEF. Thus, in vivo expression of the mutant cTnT-Q(92)protein, responsible for human HCM, impaired global cardiac systolic function in transgenic mice, which also occurred in the absence of myocyte disarray and increased interstitial collagen.
J Mol Cell Cardiol 2000 Mar
PMID:Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q(92), responsible for human hypertrophic cardiomyopathy. 1073 36

The cardiac troponin I gene has been described to be associated with hypertrophic cardiomyopathy. Until now, mutations in this gene have been found only in the Japanese population. We now present the first non-Japanese family, from northern Sweden, with a mutation in the cardiac troponin I gene. Clinical diagnose was based on echocardiography, with a maximum left ventricular wall thickness of >13 mm, or major electrocardiographic abnormalities, excluding subjects with other known causes of cardiac hypertrophy. Mutation screening was performed with a single-strand conformation polymorphism analysis and identification of mutation by direct DNA sequencing. We have identified a 33-bp deletion in exon 8 encompassing the stop codon. Nine individuals in three generations were tested, and four were carriers of this deletion. The mother was genetically affected and died of heart failure aged 90. Echocardiography at 71 years of age revealed no hypertrophy, but the electrocardiogram showed signs of left ventricular hypertrophy. Her two sons, also genetically affected, had left ventricular hypertrophy, with maximum wall thickness of 15 and 16 mm, respectively. One daughter and four grandchildren were clinically unaffected, but one of them, a 27-year-old woman with maximum wall thickness of 8 mm and normal electrocardiogram, was found to be genetically affected. In conclusion, we describe a non-Japanese family in which hypertrophic cardiomyopathy is due to a genetic defect in the cardiac troponin I gene. This mutation is a deletion of 33 bp in the last exon, whereas the previously described mutations in this gene are single nucleotide changes and a single codon deletion. The deletion of the C-terminal part of the cardiac troponin I protein, seems in this particular family to be associated with a mild phenotypic expression of familial hypertrophic cardiomyopathy.
J Mol Cell Cardiol 2000 Mar
PMID:Deletion in the cardiac troponin I gene in a family from northern Sweden with hypertrophic cardiomyopathy. 1073 50

Mutations in SCO2, a cytochrome c oxidase (COX) assembly gene located on chromosome 22, have recently been reported in patients with fatal infantile cardio-encephalomyopathy and severe COX deficiency in heart and skeletal muscle. The Sco2 protein is thought to function as a copper chaperone. To investigate the extent to which mutations in SCO2 are responsible for this phenotype, a complete sequence analysis of the gene was performed on ten patients in nine families. Mutations in SCO2 were found in three patients in two unrelated families. We detected two missense mutations, one of which (G1541A) results in an E140K substitution adjacent to the highly conserved CxxxC metal-binding site. The other (C1634T) results in an R171W substitution more distant from the copper-binding site. A nonsense codon was found on one allele in two siblings presenting with a rapidly progressive fatal cardio-encephalomyopathy. Interestingly, all patients so far reported are compound heterozygotes for the G1541A mutation, suggesting that this is either an ancient allele or a mutational hotspot. The COX deficiency in patient fibroblasts (approximately 50%) did not result in a measurable decrease in the steady-state levels of COX complex polypeptide subunits and could be rescued by transferring chromosome 22, but not other chromosomes. These data indicate that mutations in SCO2 cause a fatal infantile mitochondrial disorder characterized by hypertrophic cardiomyopathy and encephalopathy, and point to the presence of one or more other genes, perhaps in the copper delivery pathway, in this clinical phenotype.
Hum Mol Genet 2000 Mar 22
PMID:Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. 1074 87

Heart disease remains one of the leading causes of morbidity and mortality in the industrialized nations of the world. Intense investigation has centered around identifying and manipulating intracellular signaling pathways that direct hypertrophic and myopathic responses in an attempt to intervene in the progression or reverse certain forms of heart disease. We show here that cyclosporin A-mediated inhibition of the calcium-regulated phosphatase, calcineurin (PP2B), reverses cardiac hypertrophy and myopathic dilation in two transgenic mouse models of cardiomyopathy. Reversal was demonstrated by gravimetric analysis, echocardiography, histological analysis, and molecular analysis of hypertrophy-associated gene expression. In contrast, a third mouse model of hypertrophic cardiomyopathy due to activated NFAT3 cardiac-specific expression was not affected by cyclosporin A. These results suggest that calcineurin may function in the long-term maintenance of cardiac hypertrophy or myopathic disease states.
J Mol Cell Cardiol 2000 Apr
PMID:Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition. 1075 24

The properties of mutant contractile proteins that cause hypertrophic cardiomyopathy (HCM) have been investigated in expression studies and in mouse models. There is growing evidence that the precise isoforms of both the mutated protein and its interacting partners can qualitatively influence the effects of the mutation. We therefore investigated the functional effects of two HCM mutations in alpha -tropomyosin, Asp175Asn and Glu180Gly, in the in vitro motility assay using recombinant human alpha -tropomyosin, expressed with an N-terminal alanine-serine extension (AStm) to mimic acetylation in vivo, and purified native human cardiac troponin. The expected switching off of reconstituted filament movement at pCa9, and switching on at pCa5, was observed with no difference in fraction of filaments motile or filament velocity, between wild-type and mutant filaments. However, we observed increased Ca(2+)sensitivity of fraction of filaments motile using the mutant tropomyosin compared to wild-type (DeltaEC(50)+0.082+/-0. 019 pCa units for Asp175Asn and +0.115+/-0.021 for Glu180Gly). Indirect measurements using immobilized alpha -actinin to retard filament movement showed that filaments reconstituted with mutant AStm produced the same force as wild-type filaments. The results using human cardiac regulatory proteins reveal different effects of the HCM mutations in tropomyosin compared to studies using heterologous systems. By performing parallel experiments using either human cardiac or rabbit skeletal troponin we show that the cardiac-specific phenotype of HCM mutations in alpha -tropomyosin is not the result of more marked functional changes when interacting with cardiac troponin.
J Mol Cell Cardiol 2000 Aug
PMID:Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha -tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay. 1090 Jan 75

Mutations in genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). The sarcomeric protein actin plays a central, dual role in cardiac myocytes, generating contractile force by interacting with myosin and also transmitting force within and between cells. Two missense mutations in the cardiac actin gene (ACTC), postulated to impair force transmission, have been associated with familial dilated cardiomyopathy (DCM). Recently, a missense mutation in ACTC was found to cosegregate with familial HCM. To further test the hypothesis that mutations within functionally distinct domains of ACTC cause either DCM or HCM, we performed mutational analyses in 368 unrelated patients with familial or sporadic HCM. Single strand conformation polymorphism and sequence analyses of genomic DNA were performed. De novo mutations in ACTC were identified in two patients with sporadic HCM who presented with syncope in early childhood. Patients were heterozygous for missense mutations resulting in Pro164Ala and Ala331Pro amino acid substitutions, adjacent to regions of actin-actin and actin-myosin interaction, respectively. A mutation that cosegregated with familial HCM was also found, causing a Glu99Lys substitution in a weak actomyosin binding domain. The cardiac phenotype in many affected patients was characterized by an apical form of HCM. These findings support the hypothesis that a single amino acid substitution in actin causes either congestive heart failure or maladaptive cardiac hypertrophy, depending on its effect on actin structure and function.
J Mol Cell Cardiol 2000 Sep
PMID:Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy. 1096 31


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