Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years, the striking development of molecular biology and molecular genetic has brought completely new insights into the understanding of heart failure. Two aspects for which significant progress has been made in 1995 are discussed in this review: the genetic mechanisms of inherited cardiomyopathies and the molecular basis of heart failure due to chronic hemodynamic overload. In familial hypertrophic cardiomyopathy, a novel disease gene was found. It encodes myosin binding protein C, whose structure and function are poorly understood. Contractile deficits associated with the myosin mutations were demonstrated, and all this strengthened the hypothesis that hypertrophy is a compensatory mechanism that occurs in presence of a sarcomeric defect. These studies have important prognostic and clinical implications, but new and unexpected concerns have arisen, because a widespread difference in phenotype can be seen in patients harboring similar genotypes. In familial dilated cardiomyopathy, the main findings were the identification of four disease loci, but the genes are still unknown. With respect to the consequences of chronic hemodynamic overload on myocyte function and phenotype, recent data gave rise to lively discussions in the fields of reexpression of fetal troponin T isoforms and of decreased function and expression of the sarco(endo)plasmic reticulum Ca2+ ATPase in the failing human heart; at the moment it is difficult to draw definitive conclusions. Interestingly, three new concepts emerged in the understanding of the pathogenesis of heart failure: the increased contribution of the Na(+)-Ca2+ exchange, the possible recruitment of an inositol phosphate-sensitive calcium pool for myofibrillar activation, and the involvement of apoptotic myocyte and nonmyocyte cell death in myocardial remodeling.
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PMID:Molecular and cellular biology of heart failure. 883 64

Mutations in sarcomeric protein genes have been reported to cause dilated cardiomyopathy (DCM). In order to detect novel mutations we screened the sarcomeric protein genes beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2), and alpha-tropomyosin (TPM1) in 46 young patients with DCM. Mutation screening was done using single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The mutations in MYH7 were projected onto the protein data bank-structure (pdb) of myosin of striated muscle. In MYH7 two mutations (Ala223Thr and Ser642Leu) were found in two patients. Ser642Leu is part of the actin-myosin interface. Ala223Thr affects a buried residue near the ATP binding site. In MYBPC3 we found one missense mutation (Asn948Thr) in a male patient. None of the mutations were found in 88 healthy controls and in 136 patients with hypertrophic cardiomyopathy (HCM). Thus mutations in HCM causing genes are not rare in DCM and have potential for functional relevance.
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PMID:Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. 1237 28

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.
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PMID:Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. 1263 85

About 10% of cases of hypertrophic cardiomyopathy (HCM) evolve into dilated cardiomyopathy (DCM) with unknown causes. We studied 11 unrelated patients (pts) with HCM who progressed to DCM (group A) and 11 who showed "typical" HCM (group B). Mutational analysis of the beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) genes demonstrated eight mutations affecting MYH7 or MYBPC3 gene, five of which were new mutations. In group A-pts, the first new mutation occurred in the myosin head-rod junction and the second occurred in the light chain-binding site. The third new mutation leads to a MYBPC3 lacking titin and myosin binding sites. In group B, two pts with severe HCM carried two homozygous MYBPC3 mutations and one with moderate hypertrophy was a compound heterozygous for MYBPC3 gene. We identified five unreported mutations, potentially "malignant" defects as for the associated phenotypes, but no specific mutations of HCM/DCM.
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PMID:Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. 1295 Oct 62

Severe anemia, growth retardation, diabetes mellitus, cardiac disorders, and, infrequently, stroke are well-known complications of thalassemia major. We report a girl, age 7 years, 2 months, with beta-thalassemia major associated with chronic renal failure, diabetes mellitus, and cardiomyopathy in whom a silent stroke was noted during follow-up. She was diagnosed with thalassemia major at age 6 months, chronic renal failure at age 3 years, 3 months, and diabetes mellitus and cardiomyopathy at age 7 years. Although cranial computed tomography was found to be normal at the age of 3 years, 3 months, magnetic resonance imaging showed cerebral infarct in the right frontal region at 7 years, 2 months. A thrombophilic panel revealed increased factor VIII and decreased protein C concentrations. She died from disseminated intravascular coagulation at age 7 years, 9 months. We did not record any clinical findings of stroke during her follow-up. We think that diabetes mellitus, dilated cardiomyopathy, and increased factor VIII and decreased protein C concentrations led to the occurrence of cerebral infarct. In conclusion, we emphasize that children with thalassemia major should be monitored closely for stroke. We also suggest that stroke can show a silent progression in severely affected children, as in our case.
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PMID:Silent stroke in a case of beta-thalassemia major associated with chronic renal failure and diabetes mellitus. 1469 9

Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders, as well as storage diseases. A number of metabolic disorders are associated with both myopathy and cardiomyopathy. These include the glycogen storage diseases, ie, acid maltase deficiency (infantile, childhood, and adult onset), McArdle disease, and debrancher and brancher deficiencies. Disorders of lipid metabolism include systemic carnitine deficiency and abnormalities of carnitine palmitoyltransferase (CPT), long-chain acyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase. Disorders of mitochondrial metabolism affect complex I, II, III, IV and V, in addition to multiple respiratory chain defects. These may cause either hypertrophic or dilated cardiomyopathy. In addition, cardiomyopathy is frequently a component part of the storage disorders, including mucopolysaccharidosis, mucolipidosis, Fabry disease, gangliosidosis, and neuronal ceroid lipofuscinosis. Primary hypertrophic cardiomyopathy is caused by mutations in one of the genes that encode proteins of the cardiac sarcomere. Mutations in different genes are attended by different prognoses and different risks of sudden death. Mutations of the genes for myosin binding protein C (MBPC) and tropomyosin have low penetrance and cause mild forms of primary hypertrophic cardiomyopathy, while mutations of the troponin T and B-myosin genes carry a worse prognosis. Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy is usually an autosomal recessive disorder that results in the presence of abnormal Purkinje cells that interfere with normal cardiac conduction. Other conduction defects include arrhythmogenic right ventricular dysplasia (ARVD), congenital heart block, noncompaction of the left ventricle, and long Q-T syndrome (LQTS). The genetic loci for LQTS reside usually in the potassium channel, and, less frequently, in the sodium channel (channelopathies). Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.
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PMID:Review: Metabolic cardiomyopathy and conduction system defects in children. 1503 65

Combined activated protein C resistance and dilated cardiomyopathy result in a multiplicative effect on thrombosis risk. However, it is not known that whether there is an association with activated protein C resistance and dilated cardiomyopathy. We present a 18-year-old patient with dilated cardiomyopathy, who exhibited multi-chamber intracardiac thrombi on transthoracic echocardiography associated with activated protein C resistance. Our cases emphasizes that patients with cardiac thrombosis before adulthood should be screened for an underlying coagulation abnormality besides underlying cardiac disorders.
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PMID:Multi-chamber intracardiac thrombi associated with activated protein C resistance in a patient with dilated cardiomyopathy. 1637 62

Myocarditis and dilated cardiomyopathy is characterized by dilatation of all four cardiac chambers and decreased systolic function of the heart, especially in the left ventricle. In this report we presented a patient with myocarditis or dilated cardiomyopathy and deficiency of protein C and protein S with biventricular multiple intracardiac thrombi. Standard heparin infusion and acetyl salicylic acid was begun. On the 10th day of hospitalization the right ventricular thrombus disappeared, and on the 24th day all thrombi in the left ventricle disappeared. During the treatment we did not observe any complication such as hemorrhagia or embolism. We think that patients with dilated cardiomyopathy or myocarditis should be evaluated for hemostatic disorders, and should be anticoagulated if any of these disorders are presented.
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PMID:Treatment of massive cardiac thrombi in a patient with protein C and protein S deficiency. 1789 Sep 61

A number of cardiac myopathies (e.g. familial hypertrophic cardiomyopathy and dilated cardiomyopathy) are linked to mutations in cardiac muscle myosin filament proteins, including myosin and myosin binding protein C (MyBP-C). To understand the myopathies it is necessary to know the normal 3D structure of these filaments. We have carried out 3D single particle analysis of electron micrograph images of negatively stained isolated myosin filaments from rabbit cardiac muscle. Single filament images were aligned and divided into segments about 2x430A long, each of which was treated as an independent 'particle'. The resulting 40A resolution 3D reconstruction showed both axial and azimuthal (no radial) myosin head perturbations within the 430A repeat, with successive crown rotations of approximately 60 degrees , 60 degrees and 0 degrees , rather than the regular 40 degrees for an unperturbed helix. However, it is shown that the projecting density peaks appear to start at low radius from origins closer to those expected for an unperturbed helical filament, and that the azimuthal perturbation especially increases with radius. The head arrangements in rabbit cardiac myosin filaments are very similar to those in fish skeletal muscle myosin filaments, suggesting a possible general structural theme for myosin filaments in all vertebrate striated muscles (skeletal and cardiac).
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PMID:Myosin filament 3D structure in mammalian cardiac muscle. 1847 77

Of the 488 pediatric patients with thrombosis in a single center, 50 (10.2%) had nonstroke arterial thrombosis. Half of the nonstroke arterial thrombosis patients had a preceding arterial catheterization history. Infection was a common contributing underlying disorder among both catheterized and overall groups (28 and 42%, respectively). The third most common underlying risk factor for development of arterial thrombosis was associated cardiac disease, and 70% of these patients had congenital heart disease and 30% had dilated cardiomyopathy. The most common site of arterial thrombosis was the heart, and 22% of the patients developed arterial thrombosis following cardiac surgery for congenital heart diseases. The prothrombotic risk factors were also analyzed in the study group and factor V G1691A and PT G20210A heterozygous mutations were detected to be higher (16 and 4%, respectively) than those in healthy controls (7.4 and 2.3%, respectively). In addition to factor V G1691A and PT G20210A mutations, other prothrombotic risk factors including protein C and protein S deficiencies and elevated factor VIII levels were commonly associated with pediatric nonstroke arterial thrombosis cases in the present study. This finding indicates the importance of these factors in arterial thrombosis development, similar to venous thrombosis. Another striking factor of the study is the higher number of prothrombotic risk factors (more than three) in patients who had persistent thrombosis, indicating the need for more intensive treatment in these patients.
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PMID:Nonstroke arterial thrombosis in children: Hacettepe experience. 1868 35


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