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

Hypertrophic cardiomyopathy may be secondary to a mutation in the cardiac beta myosin heavy chain (14q11-q12), alpha tropomyosin (15q22), troponin T (1q32), protein C gene (11p11-q13) or in a non yet mapped gene. A X-linked dilated cardiomyopathy may be due to a mutation in the dystrophin gene (Xp21). The long QT syndrome may be secondary to a mutation in a potassium channel (7q35-36), an alpha subunit of the sodium channel gene (3p21) or in genes not yet identified (11p15.5, 4q25-q27). Marfan syndrome is associated to mutations in the fibrillin 1 gene (15q21.1) and a Marfan-like syndrome with not ocular anomalies was mapped to 3p24. Patients with Williams-Beuren syndrome have microdeletions in 7q11, whereas in the supravalvular aortic stenosis, the elastin gene which maps to the same region, is mutated. In Di George and Shprintzen syndromes but not in conotruncal malformations, microdeletions in 22q11 are observed. Heterotaxia can be transmitted by 3 types of mendelian inheritance (Xq24-q27.1). Finally, other diseases were mapped: Noonan and Holt-Oram syndromes (12q), isolated conduction blocks (19q13.3), arrhythmogenic right ventricular cardiomyopathy (14q23-q24), total anomalous pulmonary venous return (4p13-q12) and Osler-Weber-Rendu (9q33-q34.1, 3p22 and 12q1). In the near future, these incoming data will deeply modify the cardiovascular field.
 ...
PMID:[Genetics of hereditary cardiopathies]. 875 72

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. The disease is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. A large number of mutations in genes coding for the beta-myosin heavy chain (beta-MyHC), cardiac troponin T (cTnT), cardiac troponin I, alpha-tropomyosin, myosin binding protein C (MyBP-C), and myosin light chain 1 and 2 in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. The Gly256Glu, Val606Met, and Leu908Val mutations in the beta-MyHC are associated with a benign prognosis. In contrast, Arg403Gln, Arg719Trp, and Arg453Cys mutations are associated with a high incidence of sudden cardiac death (SCD). Mutations in cTnT are associated with a mild degree of hypertrophy, but a high incidence of SCD. Mutations in MyBP-C are associated with mild hypertrophy and a benign prognosis. However, it has become evident that factors other than the underlying mutations, such as genetic background and possibly environmental factors, also modulate phenotypic expression of HCM.
 ...
PMID:Molecular genetic basis of hypertrophic cardiomyopathy: genetic markers for sudden cardiac death. 947 82

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. It is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. While hypertrophy is a common cardiac response to injury, disarray is the pathological hallmark of HCM. A large number of mutations in genes coding for sarcomeric proteins, ie the beta-myosin heavy chain (beta-MyHC), cardiac troponin (cTn)T, cTnI, alpha-tropomyosin, myosin-binding protein C (MyBP-C), and essential and regulatory myosin light chains in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. Unlike mutations in the beta-MyHC gene, the prognostic significance of which reflect their hypertrophic expressivity, cTnT mutations are associated with a mild degree of hypertrophy, but a high incidence of sudden cardiac death. Mutations in MyBP-C are associated with mild hypertrophy, and a benign prognosis. However, the genetic background in which the mutations occur, and possibly environmental factors also, modulate phenotypic expression of HCM. Functional studies of mutations causing HCM have shed significant light into the pathogenesis of HCM and have led to the hypothesis that mutant sarcomeric proteins function as 'poison peptides' exerting a dominant-negative effect on the function of the cardiac myocytes, followed by structural changes and a compensatory hypertrophy.
 ...
PMID:Familial hypertrophic cardiomyopathy: a paradigm of the cardiac hypertrophic response to injury. 980 Aug 80

Hypertrophic cardiomyopathy (HCM) is defined as primary hypertrophy of the heart muscle, usually the left ventricle which is not dilated. HCM is a relatively common disease with a prevalence estimated at about 1 in 500. It is a complex disease with relatively stereotypical anatomical features but a very variable clinical presentation with a major risk of complication. All forms may be observed from almost asymptomatic hypertrophy to severe familial forms with multiple cases of sudden death. Over the last few years, molecular studies of the genetic abnormalities responsible for HCM have improved our understanding of the clinical variability of this disease. Schematically, HCM is caused by mutation of one of 4 genes which code the proteins of the sarcomere: the gene of the heavy chain of beta-myosin, the gene of cardiac T-troponin, the gene of alpha-tropomyosin and the gene of protein C linked to cardiac myosin. The main problem for clinicians is not making the diagnosis, which is relatively simple by echocardiography, but to assess the risk of complications, especially in adolescents and young adults. Patients over 40 to 45 years of age pose fewer problems as their disease is generally associated with a better prognosis since they have already survived to that age. There are many prognostic factors of sudden death, a reflection of the multifactorial character of sudden death in this disease. Four major risk factors have been identified: a family history of sudden death, abnormal blood pressure changes on exercise, a history of syncope and non-sustained ventricular tachycardia on 24 or 48-hour Holter monitoring. In children and adolescents, only the first three factors may be used, knowing that syncope, though rare, carries a very poor prognosis. On the other hand, in adults up to 40, all 4 factors are valid. Unfortunately, their positive predictive value is relatively poor, all the patients with one of these risk factors not automatically experiencing sudden death. On the other hand, their negative predictive value is excellent. Therefore, a patient with none of these factors has an excellent prognosis and should be allowed to lead a normal life. The risk is considered to be high when 2 or 3 of the factors are associated, theoretically justifying aggressive management (amiodarone? defibrillator?). Finally, there is no established management protocol in cases with a single risk factor. The discovery of mutations causing HCM will probably open up new methods of assessing the risk of sudden death in this disease. It would seem to be possible to assess the impact of the genotype on prognosis. However, this "genetic stratification" remains the realm of top research teams and is not yet accessible routinely in clinical practice.
 ...
PMID:[Evaluation of the risk of sudden death in hypertrophic cardiomyopathy]. 1032 60

Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.
 ...
PMID:The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. 1052 Dec 96

Hypertrophic cardiomyopathy (HCM) is phenotypically and genotypically heterogeneous disease of heart. Nine chromosomal loci responsible for this condition have been identified: beta-myosin heavy chain, essential and regulatory myosin light chains, troponin T and I subunits, alpha-tropomosin, cardiac myosin binding protein C, cardiac actin and titin. These genes code for proteins involved in the contraction mechanism or in the control of contraction, therefore HCM has been classified as a disease of cardiac sarcomere. Over 107 mutations have been identified. More then half of them have been detected in the beta-myosin heavy chain gene (beta-MHC). Some mutations in beta-MHC gene are associated with a benign prognosis, other are associated with high incidence of sudden cardiac death (SCD) and severe hypertrophy. Mutations in myosin binding protein C are associated with mild, delayed expression of cardiac hypertrophy and benign prognosis. Mutations in cardiac troponinT are associated with a mild degree of hypertrophy but a high incidence of SCD. Study of genes responsible for HCM will assume role in the context of clinical management of HCM, in particular regarding diagnosis and prognosis patients and families with HCM.
 ...
PMID:[Genetic changes and clinical management in familial hypertrophic cardiomyopathy]. 1080 15

Hypertrophic cardiomyopathy (HCM) is a heterogenous disease, with variable genotypic and phenotypic expressions, often caused by mutations in sarcomeric protein genes. The aim of this study was to identify the genotypes and associated phenotypes related to HCM in northern Sweden. In 46 unrelated individuals with familial or sporadic HCM, mutation analysis of eight sarcomeric protein genes was performed; the cardiac beta-myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, alpha-tropomyosin, cardiac essential and regulatory myosin light chains, cardiac troponin I and cardiac alpha-actin. A total of 11 mutations, of which six were novel ones, were found in 13 individuals. Seven mutations were located in the myosin-binding protein C gene, two in the beta-myosin heavy chain gene and one in the regulatory myosin light chain and troponin I genes, respectively. This is the first Swedish study, where a population with HCM has been genotyped. Mutations in the cardiac myosin-binding protein C gene were the most common ones found in northern Sweden, whereas mutations in the beta-myosin heavy chain gene were less frequent than previously described. There are differences in the phenotypes mediated by these genes characterised by a more late-onset disease for the myosin-binding protein C gene mutations. This should be taken into consideration, when evaluating clinical findings in the diagnosis of the disease, especially in young adults in families with HCM, where penetrance can be expected to be incomplete in the presence of a myosin-binding protein C gene mutation.
 ...
PMID:Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. 1281 75

Hypertrophic cardiomyopathy is associated with marked genetic and phenotypic heterogeneity. Pathogenic mutations in the 10 hypertrophic cardiomyopathy-associated sarcomeric genes cause autosomal dominant disease as a rule, although recessive disease has been reported. Cardiac hypertrophy is also a hallmark of Friedreich ataxia, an autosomal recessive disease caused by deficiency of the mitochondrial protein frataxin. We hypothesized that heterozygous mutations in frataxin may mimic or modify hypertrophic cardiomyopathy. Using DHPLC and DNA sequencing, we identified the novel R40C-frataxin mutation in a patient who also harbored a previously reported R810H-myosin binding protein C mutation. The R810H mutation is reported to cause hypertrophic cardiomyopathy only in the setting of homozygosity or compound heterozygosity with another sarcomeric mutation. Site-directed mutagenesis and in vitro and in vivo analysis enabled functional characterization of the mutant frataxin protein. R40C-frataxin protein is not cleaved to the mature form in vitro and shows delayed kinetics of cleavage by isolated mouse mitochondria. Yeast cells expressing R40C-frataxin demonstrated increased sensitivity to oxidative stress and abnormal accumulation of precursor frataxin protein. These data indicate that frataxin deficiency may have contributed to this patient's particular phenotype. Furthermore, these findings suggest that mutations altering myocyte energetics may act in synergy with sarcomeric mutations to cause hypertrophic cardiomyopathy.
 ...
PMID:Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy. 1593 68

Hypertrophic cardiomyopathy (HCM) is one of the most common causes of sudden cardiac death in young adults and is a familial disease in at least 60% of cases. Causative mutations have been identified in several sarcomeric genes, including the myosin binding protein C (MYBPC3) gene. Although numerous causative mutations have been identified, the pathogenetic process is still poorly understood. A large animal model of familial HCM in the cat has been identified and may be used for additional study. As the first spontaneous large animal model of this familial disease, feline familial HCM provides a valuable model for investigators to evaluate pathophysiologic processes and therapeutic (pharmacologic or genetic) manipulations. The MYBPC3 gene was chosen as a candidate gene in this model after identifying a reduction in the protein in myocardium from affected cats in comparison to control cats (P<0.001). DNA sequencing was performed and sequence alterations were evaluated for evidence that they changed the amino acid produced, that the amino acid was conserved and that the protein structure was altered. We identified a single base pair change (G to C) in the feline MYBPC3 gene in affected cats that computationally alters the protein conformation of this gene and results in sarcomeric disorganization. We have identified a causative mutation in the feline MYBPC3 gene that results in the development of familial HCM. This is the first report of a spontaneous mutation causing HCM in a non-human species. It should provide a valuable model for evaluating pathophysiologic processes and therapeutic manipulations.
 ...
PMID:A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. 1623 61

Hypertrophic cardiomyopathy is an autosomal dominant inherited disease characterized by ventricular hypertrophy and myofibril disarray. Mutations responsible for hypertrophic cardiomyopathy have been identified in 11 genes that encode for cardiac sarcomere proteins. Traditionally, hypertrophic cardiomyopathy due to mutation of the myosin-binding protein C gene (MYBPC3) has been thought to follow a benign course. We report a family with several members affected by hypertrophic cardiomyopathy in which there was a high incidence of sudden death. Disease was presumably caused by the substitution of cytosine by guanine at nucleotide 269 of MYBPC3 mRNA. This mutation, which has not previously been described, modifies codon 79, which encodes for the incorporation of a tyrosine, and gives rise to a stop codon. The mutation described here appears to confer a higher risk than that previously associated with hypertrophic cardiomyopathy due to MYBPC3 gene mutation.
 ...
PMID:[High-risk hypertrophic cardiomyopathy associated with a novel mutation in cardiac Myosin-binding protein C]. 1739 78


1 2 3 Next >>