Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hypertrophic cardiomyopathy is an autosomal dominant disorder manifesting as cardiac hypertrophy in the absence of increased cardiac work load, which has been studied as a model of myocardial hypertrophy in humans. Hypertrophic cardiomyopathy is genetically heterogeneous with three known disease-genes and two further mapped loci. The disease-genes encode contractile proteins of the thick and thin filaments of the sarcomere: the beta cardiac myosin heavy chain gene on chromosome 14q11, the alpha tropomyosin gene on chromosome 15q2 and the cardiac troponin T gene on chromosome 1q3. Other disease loci have been mapped to chromosome 11p13-q13 and 7q3. In each known disease-gene a number of different mutations have been identified; these are missense mutations, or mutations leading to modest alterations of peptide structure, but not null alleles. Specific mutations are associated with different disease severity and may provide diagnostic and prognostic information not available from clinical assessment. Genetic and functional data suggest that mutations which cause hypertrophic cardiomyopathy act as dominant negative alleles that impair cross-bridge cycling and contractile function and interfere with sarcomere assembly.
Hum Mol Genet 1995
PMID:Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. 854 71

The transition of cardiac muscle myofilament activity from the diastolic to the systolic state is a complex allosteric/co-operative process, rich in potential control mechanisms. The rate and intensity of the transition is modulated by the mechanical state of the myofilaments, by covalent and non-covalent mechanisms, and by the isoform population of myofilament proteins. Moreover, the process is altered in pathological states and subject to modification by pharmacological agents with potential use as inotropic drugs. We present here a current perception of the process, with focus on molecular interactions of the thin filament components, especially troponin I. Our discussion is couched in terms of what we believe to be pressing questions in the current state of knowledge of this system. These questions are as follows: what is the topology of the thin filament and how do thin filament proteins regulate the activation of cross-bridge cycling? What is the relative role of protein phosphorylation of thin filament proteins in the regulation of the cardiac activity and dynamics? What is the relative role of feedback effects of cross-bridge binding on thin filament activity? Answers to these questions have taken on new significance, with the identification of familial hypertrophic cardiomyopathy as a "sarcomeric" disease related to missense mutations in myosin, troponin T. and tropomyosin. As discussed, new and exciting developments in this area are bringing us closer to the answers to these questions.
J Mol Cell Cardiol 1996 Feb
PMID:Altered interactions among thin filament proteins modulate cardiac function. 887 93

We recently reported that protein kinase C (PKC) potentiates cAMP-dependent phosphodiesterase (PDE) activity in Syrian hamster hearts with hypertrophic cardiomyopathy (HCM) but not in control hamster hearts. In this study, we examined the mechanism of this PKC/PDE interaction by identifying the PDE isozyme that is the target of PKC modulation. Using Mono-Q high performance liquid chromatography, both control and HCM hamster cardiac PDE could be partially purified into the calcium/calmodulin-dependent (I), the cGMP-stimulated (II), and the low KM (III) isozyme fractions. The elution profiles of PDE isozyme fractions were similar to those in isolated hamster cardiac myocytes. The percentages of PDE isozymes activities (I/II/III) were 68.8:22.4:8.8% and 51.1:38.4:10.5% for HCM and control hearts, respectively (n = 4), suggesting a change in the quantitative expression of isozymes activities in HCM hearts with a significant increase in the calcium/calmodulin-dependent PDE isozyme activities (p < 0.05 compared with control). The addition of exogenous PKC (100 munits of rat brain) produced a 60% stimulation in the calcium/calmodulin-dependent PDE isozyme fraction but not in other PDE isozymes of HCM and in none of the isozymes in control hearts. This PKC-mediated potentiation of the calcium/calmodulin-dependent PDE activity was completely blocked by the PKC-specific peptide inhibitor PKC(19-31). Analysis of enzymatic kinetics showed that PKC enhanced the calcium/calmodulin-dependent PDE isozyme activity in HCM by increasing its Vmax (from 350 pmol/mg/min at baseline to 758 pmol/min/mg with PKC) without changing its KM (0.69 microM at baseline versus 0.89 microM with PKC). These results suggest that there are both quantitative and qualitative abnormalities in the expression of the calcium/ calmodulin-dependent PDE isozyme in HCM hearts and that the PKC modulation of PDE activity in the HCM heart is isozyme specific.
Mol Pharmacol 1996 Sep
PMID:Cyclic AMP-dependent phosphodiesterase isozyme-specific potentiation by protein kinase C in hypertrophic cardiomyopathic hamster hearts. 879 93

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a severe defect of mitochondrial fatty acid oxidation characterized by hypertrophic cardiomyopathy, pericardial effusion, steatosis, and hypoglycemia, often resulting in death by 4-5 months of age. The onset of cardiomyopathy and pericardial effusion is insidious and sudden, necessitating early diagnosis and intervention to prevent death. A family affected with this defect is described in which dietary therapy with medium-chain triglycerides (MCT) was associated with rapid reversal of these severe clinical symptoms. Diagnosis by acylcarnitine analysis in the neonatal period can provide the opportunity for early clinical intervention. Prenatal diagnosis from amniocytes by enzymology or in vitro analysis of the fat oxidation pathway with deuterated fatty acid precursors has also been successful and permits intervention at birth. Of 10 affected children, 7 untreated cases died within the first several months while the remaining 3 cases survived when treated with medium-chain triglycerides as the major source of dietary fat.
Biochem Mol Med 1996 Jun
PMID:Very long chain acyl-CoA dehydrogenase deficiency: successful treatment of acute cardiomyopathy. 880 47

Mutations in the cardiac beta-myosin heavy chain (MHC) gene of 50 Japanese patients with hypertrophic cardiomyopathy (HCM) were investigated by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. A novel deletion mutation was detected in exon 3 of the cardiac beta-MHC gene in a Japanese family with HCM. Sequencing analysis revealed a three nucleotide deletion at codon 10 leading to a deletion of a glycine residue, which has been conserved in the myosin gene from birds to humans. Because this deletion mutation was not detected in other healthy family members, it was suggested that this 10Gly deletion is the cause of HCM in this family. The same deletion mutation has been found in three other unrelated patients with HCM. This is the first report of a one codon deletion in the beta-MHC gene in patients with HCM.
J Mol Cell Cardiol 1995 Dec
PMID:A novel deletion mutation in the beta-myosin heavy chain gene found in Japanese patients with hypertrophic cardiomyopathy. 882 81

Familial hypertrophic cardiomyopathy is the first primary cardiomyopathy to have yielded to the techniques of modern molecular genetics. In the past few years, four genes responsible for this disease have been identified, all of which code for sarcomeric structural proteins. In addition, structure-function analysis and genotype-phenotype correlation studies have shed significant light on the molecular basis of this disease. It is hoped that within the next few years the application of molecular genetic tools will not only facilitate the diagnosis of hypertrophic cardiomyopathy but will also provide prognostic and therapeutic stratification for more definitive therapy.
Mol Med Today 1996 Sep
PMID:Familial hypertrophic cardiomyopathy: diagnostic and therapeutic implications of recent genetic studies. 888 58

The exons 13, 16, 21 and 23 of cardiac beta-myosin heavy chain (MHC) gene from 32 Chinese patients with hypertrophic cardiomyopathy were analyzed by the polymerase chain reaction and the DNA single strand conformation polymorphism (PCR-SSCP) procedure. The results showed an altered SSCP in exon 13 of one patient. Sequencing analysis revealed that the patient had a G to T transversion in codon 383, resulting in the substitution of Lys by Asn. The missense mutation was also confirmed by Southern blot hybridization with an allele-specific oligonucleotide probe. Because it was found at a residue highly conserved through evolution, this mutation is likely to be the cause of hypertrophic cardiomyopathy in the patient. Because her parents and child were neither clinically nor genetically affected, it was concluded that the mutation in this patient arose de novo and was not passed to her child. This is the first report of a mutant cardiac beta-MHC gene in the Chinese population. Also, it is a novel missense mutation of the cardiac beta-MHC gene.
J Mol Cell Cardiol 1996 Sep
PMID:Identification of a novel missense mutation in the cardiac beta-myosin heavy chain gene in a Chinese patient with sporadic hypertrophic cardiomyopathy. 889 46

Hereditary hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, but the genetic defects are still unclear in many cases. Reduced myocardial long-chain fatty acid (LCFA) uptake has been demonstrated in patients with some types of HCM. In addition, a possible relationship between a shift ofmyocardial substrate utilization and cardiac hypertrophy has been suggested by experimental studies. Myocardial uptake of LCFAs occurs via a specific transporter, which is homologous with human CD36. CD36 deficiency has also been reported in some individuals, and is transmitted as an autosomal dominant trait like HCM. In this study, we analyzed CD36 in 47 patients with HCM [29 with asymmetric septal hypertrophy (ASH) and 18 without ASH], 11 patients with dilated cardiomyopathy (DCM), and 26 patients with pressure-overload cardiac hypertrophy. Eleven patients (37.9%) who had HCM with ASH, one (9.1%) with DCM, and two (7.7%) with pressure-overload hypertrophy showed CD36 deficiency, while none of the HCM patients without ASH had CD36 deficiency. One patient who had HCM with ASH and CD36 deficiency showed no myocardial LCFA uptake, although myocardial perfusion was normal. Reduced myocardial LCFA uptake despite normal myocardial perfusion was demonstrated in the other HCM patients with ASH and CD36 deficiency. Based on the high prevalence of CD36 deficiency in HCM patients with ASH, we hypothesize that this deficiency might be one etiology of hereditary HCM.
J Mol Cell Cardiol 1997 Jan
PMID:Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? 904 27

A trinucleotide repeat polymorphism in the MEF2A gene is described. MEF2A is expressed early in cardiac muscle development; thus the possibility of linkage between this polymorphism and familial cardiomyopathies was investigated in three families not linked to genes coding for known sarcomeric proteins. MEF2A was excluded as a candidate for dilated cardiomyopathy (DCM)(LOD of -9.03) and hypertrophic cardiomyopathy (HCM)(LODs of -5.43 and -2.44) in these families. Because expansion of triplet repeats has been shown to be responsible for several inherited diseases, 121 unrelated HCM probands and 28 unrelated DCM probands were examined for evidence of expansion of this repeat. No expansion of this trinucleotide repeat was seen in any of the 149 cardiomyopathy probands.
Mol Cell Probes 1997 Feb
PMID:Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies. 907 15

Several mutations in the beta-myosin heavy chain (beta-MHC) gene have been linked to hypertrophic cardiomyopathy (HCM). Because this gene is also expressed in slow-twitch fibers of skeletal muscle, we have been able to study the mutant beta-myosin content and mechanical properties associated with these myosin mutations in single skinned skeletal muscle fibers obtained from HCM patients. We found that in patients carrying the 403Arg-->Gln mutation, the mutant beta-MHC comprises 47.3 +/- 9.1% of the total beta-MHC present in single slow-twitch fibers. Therefore, both alleles of the beta-MHC gene are on average equally expressed. Isometric tension was decreased by 18% in slow fibers from HCM patients with the 403Arg-->Gln mutation, but was unchanged in slow fibers from patients with two other beta-MHC gene mutations. Taken together with the previous demonstration of reduced velocities generated by these myosins in an in vitro assay, our results suggest that the mutant beta-myosins are functional molecular motors that are able to generate tension and movement, but with abnormal kinetics.
J Mol Cell Cardiol 1997 Feb
PMID:Isometric tension and mutant myosin heavy chain content in single skeletal myofibers from hypertrophic cardiomyopathy patients. 914 Aug 24


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