Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation. A total of 23 individuals were diagnosed as carriers, and seven were obligate carriers or had been clinically diagnosed. The Arg723Gly mutation was associated with a malignant phenotype. Ten out of 30 affected members died suddenly or needed an implantable cardioverter-defibrillator at a mean age of 42, and seven members developed progressive heart failure, leading to death or heart transplant in five, at a mean age of 50 years. Echocardiography showed non-obstructive left ventricular hypertrophy in affected members older than 20 (sensitivity 68%). Mean survival of affected members was 51 years. In conclusion, a new mutation Arg723Gly in beta-myosin heavy chain gene is reported which shortens life expectancy because of sudden death and end-stage heart failure.
J Mol Cell Cardiol 2000 Dec
PMID:Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene. 1111 6

Patients with hypertrophic cardiomyopathy (HCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity, which is partly due to the diversity of causal mutations, genetic background (modifier genes), and probably environmental factors. We determined association of functional variants of tumor necrosis factor (TNF)- alpha, interleukin-6 (IL6), insulin-like growth factor-2 (IGF2), transforming growth factor- beta 1 (TGFB1), and aldosterone synthase (CYP11B2) genes, all previously implicated in cardiac hypertrophy, with the severity of LVH in patients with HCM. Two-dimensional echocardiography was performed and demographic variables were recorded in 142 genetically independent patients. Indices of LVH including interventricular septal thickness (IVST), left ventricular mass index (LVMI), and LVH score were measured/calculated. TNF-alpha-308G/A, IL6-174G/C, IGF2 820G/A, TGFB1-509C/T, and CYP11B2-344T/C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were identified by the presence of specific electrophoretic patterns and their distributions were according to the Hardy-Weinberg equilibrium. Demographic variables were not significantly different among the genotypes. Subjects with the AA genotype of TNF-alpha (n=8) were approximately 13 years younger at the time of clinical diagnosis. Despite a younger age, they had a greater mean LVMI than those with the GG (n=94) or GA (n=33) genotypes (191.8+/-59.5 v 139.1+/-47.3 v 132.1+/-34.3, respectively, P=0.004). TNF-alpha-308G/A genotypes accounted for 6.0% of variability of LVMI (P=0.002). Mean IVST, LVEDD, and LVH score were not significantly different. Variants of IL6, IGF2, TGFB1, and CYP11B2 were not associated with indices of LVH. The uncommon allele of TNF-alpha-308G/A polymorphism, known to produce more TNF- alpha, was associated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicated in cardiac hypertrophy, were not associated with the indices of LVH. These results suggest that TNF-alpha is a modifier gene for HCM.
J Mol Cell Cardiol 2000 Dec
PMID:Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. 1111 12

Hypertrophic cardiomyopathy occurs in two variants, either as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. Different genes coding sarcomeric proteins of the heart have been identified as causing hypertrophic cardiomyopathy. Missense mutations in the cardiac beta-myosin heavy chain gene are found in 30% of all cases of familial hypertrophic cardiomyopathy. We screened the beta-myosin heavy chain gene of children of nine Austrian families with hypertrophic cardiomyopathy (referred to as group A) and of seven children with sporadic hypertrophic cardiomyopathy (referred to as group B). We were able to find two previously described (V606M, R453C) and two unknown missense mutations (V406M, R663H) in group A. Additionally, in two children of group B we could identify one already known missense mutation, R249Q as well as one previously unknown missense mutation, M877K. The genetically affected children of group A developed no or only mild clinical symptoms, whereas the children of group B with genetically confirmed sporadic hypertrophic cardiomyopathy showed manifest left ventricular hypertrophy and clinical symptoms including chest pain and dyspnoea. Clinical symptoms among the adults of group A, suffering from familial hypertrophic cardiomyopathy, varied significantly. We therefore believe V406M to be a more malignant missense mutation, probably linked with sudden death in the affected family, than R663H, which seems to be more benign causing late-onset hypertrophic cardiomyopathy and mild clinical symptoms in the affected family members.
J Mol Cell Cardiol 2001 Jan
PMID:Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children. 1113 30

Mutations have been identified in alpha-tropomyosin (Tm), a key regulatory protein in striated muscle cells, that are associated with a human cardiac myopathy, hypertrophic cardiomyopathy (FHC) and a human skeletal myopathy, nemaline myopathy (NM). In this review, we highlight experiments aimed at identifying the underlying mechanisms by which mutations in alpha-Tm cause inherited diseases of cardiac and skeletal muscle. Gene transfer of normal and mutant alpha-Tm to isolated adult cardiac myocytes was used to study the primary effects of mutant alpha-Tm proteins on the structure and contractile function of fully differentiated striated muscle cells. Both FHC and NM mutant alpha-Tm proteins incorporated normally into the adult muscle sarcomere, similar to normal Tm but exerted differential "dominant-negative" effects on the contractile function of the muscle cell. FHC mutant alpha-Tm proteins produced hypersensitivity of Ca2+-activated force production with a hierarchy that was related to the clinical severity of each mutation. Conversely, the NM mutant alpha-Tm produced a hyposensitivity of Ca2+-activated force production that may underlie, at least in part, the muscle weakness observed in NM. Taken together, the results suggest that the differential changes in the ability of the mutant Tm proteins to regulate muscle contraction in response to changing Ca2+ concentrations underlie the differential clinical presentation of the cardiac and skeletal muscle myopathies associated with mutations in alpha-Tm.
J Mol Med (Berl) 2000
PMID:Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies. 1119 27

Friedreich's ataxia is an autosomal recessive disorder characterized by spinocerebellar degeneration. It is caused by an unstable GAA trinucleotide repeat expansion (>120 repeats) in the first intron of the frataxin gene on chromosome 9 (9q13) in both alleles. Concentric left ventricular hypertrophy has been recognized as the major cardiac manifestation of Friedreich's ataxia. Our aim was to investigate the influence of the frataxin repeat length on cardiac hypertrophy in patients with Friedreich's ataxia and in patients with hypertrophic and dilated cardiomyopathy. Thirty-one patients with Friedreich's ataxia, 86 patients with hypertrophic cardiomyopathy, 134 patients with dilated cardiomyopathy, and 32 healthy individuals without cardiac disease were analysed by electrocardiography and 2D-M-mode echocardiography. Then, the size of the frataxin repeat was determined by polymerase chain reaction (PCR) and agarose gel electrophoresis. The number of GAA repeats in patients with hypertrophic and dilated cardiomyopathy was not different from the length in patients without cardiac disease (hypertrophic cardiomyopathy, 8+/-2 repeats on GAA 1 allele and 11+/-5 repeats on GAA 2 allele; dilated cardiomyopathy, 7+/-2 repeats on GAA 1 allele and 11+/-5 repeats on GAA 2 allele; Control, 9+/-1 repeats on GAA 1 allele and 12+/-6 repeats on GAA 2 allele). The septal and posterior wall thickness of these patients was not related to the GAA repeat length. All patients with Friedreich's ataxia had two enlarged alleles with a mean GAA repeat length of 757+/-316 and 1012+/-231, respectively. The lengths of both alleles were significantly greater than the lengths in the controls (P<0.0001), patients with hypertrophic cardiomyopathy (P<0.0001) and dilated cardiomyopathy (P<0.0001). A significant correlation was revealed between interventricular septal hypertrophy and frataxin repeat length in the smaller allele. Furthermore, the ratio of septal to posterior wall thickness was significantly correlated to GAA repeat size on the smaller allele. In conclusion, the size of the GAA repeat on the smaller allele in the frataxin gene is associated with the degree of left ventricular hypertrophy in patients with Friedreich's ataxia but is not related to the severity of hypertrophic cardiomyopathy.
J Mol Med (Berl) 2001
PMID:The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich's ataxia. 1126 9

Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. HCM is the most common cause of sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly. Hypertrophy and fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric proteins. The beta -myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype-phenotype correlation studies suggest that mutations in the beta -MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood. In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced ATPase activity of myosin, acto-myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+ sensitivity. Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.
J Mol Cell Cardiol 2001 Apr
PMID:The molecular genetic basis for hypertrophic cardiomyopathy. 1127 20

Proteins in cardiac myocytes assemble into contractile units known as sarcomeres. Contractile force is generated by interaction between sarcomeric thick and thin filaments. Thin filaments also transmit force within and between myocytes. Mutations in genes encoding the thin filament proteins actin and tropomyosin cause hypertrophic cardiomyopathy. Mutations affecting functionally distinct domains of actin also cause dilated cardiomyopathy (DCM). We used a non-positional candidate gene approach to test further the hypothesis that dysfunction of sarcomeric thin filaments, due to different mutations in the same gene, can lead to either hypertrophic or dilated cardiomyopathy. Mutational analyses of alpha-tropomyosin 1 were performed in patients with idiopathic DCM. We identified two mutations that alter highly conserved residues and that, unlike hypertrophic cardiomyopathy-associated mutations, cause localized charge reversal on the surface of tropomyosin. Therefore, substitution of different amino acid residues in the same thin filament proteins is associated with the distinct phenotypes of cardiac hypertrophy or congestive heart failure.
J Mol Cell Cardiol 2001 Apr
PMID:Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. 1127 25

Friedreich's ataxia is an autosomal recessive neuro-degenerative disorder involving both central and peripheral nervous system. Patients also show a systemic clinical picture presenting heart disease and diabetes mellitus or glucose intolerance. The disease is caused by mutations in the FRDA gene mapped on chromosome 9q13. The product of the gene is frataxin, an 18 kDa soluble mitochondrial protein with 210 amino acids. Crystal structure suggests a new, not previously reported, protein fold. The most frequent mutation is the expansion of a GAA trinucleotide repeat located within the first intron of the gene, and represents 98% of the mutations. Point mutations are described in compound heterozygous subjects with one expanded allele. A two-step model of GAA normal alleles towards premutation alleles, which might generate further full expanded mutations in the population with Indo-European ancestry, has been postulated. Clinical phenotype is variable and an inverse correlation with the GAA expansion size has been observed. Analysis of the GAA triplet is a strong molecular tool for clinical diagnosis, genetic counselling and prenatal diagnosis. Friedreich's ataxia patho-genesis is not solved yet. Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. Iron is accumulated in the mitochondrial matrix of both the yeast frataxin deficient mutant and the patient fibroblasts. It has been postulated that iron-induced oxygen radical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology. A second hypothesis postulates a direct role of frataxin in the mitochondrial energy activation and oxidative phosphorylation. Iron chelator drugs and antioxidant drugs have been postulated for Friedreich's treatment. No results from clinical trials are available yet, but idebenone, a short-chain quinone, seems to reduce the size of hypertrophic cardiomyopathy and levels of oxidative stress molecules in patients.
Int J Mol Med 2001 Jun
PMID:Friedreich's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review). 1135 Dec 69

A suppressor mutation, D53, of the held-up(2) allele of the Drosophila melanogaster Troponin I (wupA) gene is described. D53, a missense mutation, S185F, of the tropomyosin-2, Tm2, gene fully suppresses all the phenotypic effects of held-up(2), including the destructive hypercontraction of the indirect flight muscles (IFMs), a lack of jumping, the progressive myopathy of the walking muscles, and reductions in larval crawling and feeding behavior. The suppressor restores normal function of the IFMs, but flight ability decreases with age and correlates with an unusual, progressive structural collapse of the myofibrillar lattice starting at the center. The S185F substitution in Tm2 is close to a troponin T binding site on tropomyosin. Models to explain suppression by D53, derived from current knowledge of the vertebrate troponin-tropomyosin complex structure and functions, are discussed. The effects of S185F are compared with those of two mutations in residues 175 and 180 of human alpha-tropomyosin 1 which cause familial hypertrophic cardiomyopathy (HCM).
Mol Biol Cell 2001 May
PMID:A tropomyosin-2 mutation suppresses a troponin I myopathy in Drosophila. 1135 41

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.
Hum Mol Genet 2001 May 15
PMID:Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. 1137 14


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