Gene/Protein Disease Symptom Drug Enzyme Compound
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The majority of familial hypertrophic cardiomyopathy patients carrying a mutation in the cardiac myosin binding protein C gene show low penetrance, late onset of the disease and a relatively benign phenotype. Sudden death in these patients, if it occurs, usually takes place after the fifth or sixth decade of life and can be precipitated by stress. Previously, we prepared mice carrying a mutated MyBP-C lacking both the titin and myosin binding sites at the carboxyl terminus. This mutation is found in some familial hypertrophic cardiomyopathy patients and the mice develop some symptoms that are consistent with the disease. In the present study, we wished to determine the response of these animals to various forms of cardiovascular stress. Consistent with the human disease presentation, only a mild cardiac hypertrophy was detected in unstressed animals. Although there are no complementary human data with which to compare the mice, molecular signs of stress were apparent in the animals, as increased levels of the intermediate filament protein, desmin and the chaperone protein, alpha-B-crystallin, were present in the hearts. To determine whether the animals were sensitive to stress, they were subjected to sub-maximal treadmill exercise or to chronic isoproterenol infusion. The affected mice were significantly compromised in their exercise capacity and showed an impaired response during isoproterenol infusion. Increased mortality was observed during the exercise regimen, with some animals experiencing sudden death. We conclude that the mouse model recapitulates some of the known aspects of the human disease, particularly its late onset and benign phenotype. However, cardiac stress can lead to severe bradycardia and death.
J Mol Cell Cardiol 2001 Sep
PMID:Phenotypic deficits in mice expressing a myosin binding protein C lacking the titin and myosin binding domains. 1154 36

Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca(2+)-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and alpha-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in alpha-tropomyosin; this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wild-type alpha-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous alpha-tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in alpha-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.
J Mol Cell Cardiol 2001 Oct
PMID:A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. 1160 24

Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder caused by mutationally altered dominant-acting sarcomere proteins, exhibits significant clinical heterogeneity. To determine whether genetic background could influence the expression of this disease, we studied a murine model for this human condition. Hypertrophic responses to the Arg403Gln missense mutation in a cardiac myosin heavy chain gene were compared in 129SvEv (inbred; designated 129SvEv- alpha MHC403/+) and Black Swiss (outbred; designated BSw- alpha MHC403/+) strains. At 30-50 weeks of age all 129SvEv- alpha MHC403/+ showed left ventricular hypertrophy, while left ventricular wall thickness was increased in only half of BSw- alpha MHC403/+ mice demonstrating that a polymorphic modifier gene can determine the hypertrophic response to this dominant-acting sarcomere protein mutation. Further analysis suggests that SJL/J mice bear a recessive allele of this modifier gene that prevents a hypertrophic response to the Arg403Gln missense mutation. We conclude that genetic modifiers in mice, and presumably in man, can alter the hypertrophic response to sarcomere protein gene missense mutations.
J Mol Cell Cardiol 2001 Nov
PMID:A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy. 1170 49

Functional consequences of the six mutations (R145G, R145Q, R162W, DeltaK183, G203S, K206Q) in cardiac troponin I (cTnI) that cause familial hypertrophic cardiomyopathy (HCM) were studied using purified recombinant human cTnI. The missense mutations R145G and R145Q in the inhibitory region of cTnI reduced the intrinsic inhibitory activity of cTnI without changing the apparent affinity for actin. On the other hand, the missense mutation R162W in the second troponin C binding region and the deletion mutation DeltaK183 near the second actin-tropomyosin region reduced the apparent affinity of cTnI for actin without changing the intrinsic inhibitory activity. Ca(2+) titration of a fluorescent probe-labeled human cardiac troponin C (cTnC) showed that only R162W mutation impaired the cTnC-cTnI interaction determining the Ca(2+) affinity of the N-terminal regulatory domain of cTnC. Exchanging the human cardiac troponin into isolated cardiac myofibrils or skinned cardiac muscle fibers showed that the mutations R145G, R145Q, R162W, DeltaK183 and K206Q induced a definite increase in the Ca(2+)-sensitivity of myofibrillar ATPase activity and force generation in skinned muscle fibers. Although the mutation G203S also showed a tendency to increase the Ca(2+) sensitivity in both myofibrils and skinned muscle fibers, no statistically significant difference compared with wild-type cTnI could be detected. These results demonstrated that most of the HCM-linked cTnI mutations did affect the regulatory processes involving the cTnI molecule, and that at least five mutations (R145G, R145Q, R162W, DeltaK183, K206Q) increased the Ca(2+) sensitivity of cardiac muscle contraction.
J Mol Cell Cardiol 2001 Dec
PMID:Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy. 1173 57

Cardiomyopathies are a group of disorders that result in dysfunction of the contractility of the myocardium anda decrease in cardiac function. Cardiomyopathies may be primary or idiopathic or secondary due to an underlying definable systemic disorder. Cardiomyopathies may be further defined as according to the World Health Organization (WHO) as: 1) congestive or dilated; 2) obstructive as in hypertrophic cardiomyopathy; 3) restrictive as in infiltrative disorders such as storage diseases. Two additional categories have been added that include arrhythmogenic right ventricular cardiomyopathy and unclassified cardiomyopathies. A number of metabolic disorders result in cardiomyopathy and are frequently the cause of death in these disorders.
Pediatr Pathol Mol Med
PMID:Cardiovascular involvement in metabolic diseases. 1194 39

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.
J Mol Cell Cardiol 2002 Jul
PMID:Transgenic rabbits expressing mutant essential light chain do not develop hypertrophic cardiomyopathy. 1209 25

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A-->C, IVS14-13G-->A, Ex25DeltaLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A-->C), a novel substitution in intron 14 (IVS14-13G-->A), and a novel 3-bp deletion in exon 25 (Ex25DeltaLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations.
J Mol Med (Berl) 2002 Jul
PMID:Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland. 1211 Sep 47

In recent years, the main focus of human genetic studies on hypertrophic cardiomyopathy (HCM) switched from discovering novel genes and defining disease-causing mutations to studies of mutation distribution in disease populations. Eventually these studies will define genotype-phenotype relationships, which may provide clues to understanding the disease process and help to select the most appropriate treatment strategy. Animal models engineered to recapitulate human disease provide a unique tool to investigate the pathogenic mechanisms and evaluate potential therapies. In this review, we present the spectrum of clinical HCM in the context of the genetic heterogeneity of this common human disease. Recent progress made in understanding molecular pathways that result in cardiac hypertrophy and the factors that modify these processes are discussed.
Hum Mol Genet 2002 Oct 01
PMID:Phenotypic diversity in hypertrophic cardiomyopathy. 1235 86

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.
Hum Mol Genet 2002 Nov 15
PMID:A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. 1241 27

Myocardial disorders are major causes of morbidity and mortality, including heart failure, sudden death and the need for heart transplantation. The two most common forms of myocardial disorders, dilated cardiomyopathy and hypertrophic cardiomyopathy are paradigms of left ventricular systolic dysfunction and diastolic dysfunction. The genetics of these disorders are increasingly understood with the sarcomere playing a central role in the development of HCM and the link between sarcomere and sarcolemma being key to the development of DCM. In this review, the genetics of the myocardial diseases will be described.
Expert Rev Mol Diagn 2002 Nov
PMID:Molecular diagnosis of myocardial disease. 1246 55


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