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)

Idiopathic cardiomyopathy is reviewed from molecular standpoint. About a half of all patients with hypertrophic cardiomyopathy show intra-familial occurrence. In familial hypertrophic cardiomyopathy, nine gene abnormalities have been discovered in the sarcomere, i.e. the genes of beta cardiac myosin heavy chain, cardiac troponin T, alpha-tropomyosin, cardiac myosin binding protein-C, essential or regulatory myosin light chain, cardac troponin I, alpha-cardiac actin, and titin. Sudden death can occur in patients with familial-type hypertrophic cardiomyopathy with abnormalities of the cardiac troponin T or troponin I gene, even if hypertrophy is not marked. Some cases of familial dilated cardiomyopathy show gene abnormalities for cytoskeletal components such as desmin and laminin A/C. Mutations of the delta-sarcoglycan gene have also been discovered in familial or sporadic dilated cardiomyopathy. Mutations in mitochondrial genes have been observed in both hypertrophic and dilated cardiomyopathy. It is postulated that chronic viral myocarditis may sometimes lead to dilated cardiomyopathy, and hepatitis C virus is also thought to be an etiological factor. Immunological abnormalities have also been reported, such as autoantibodies against myosin, beta-receptors, ADP/ATP carrier proteins.
Int J Mol Med 2003 Jan
PMID:Cardiomyopathy: molecular and immunological aspects (review). 1246 10

The diagnostic value of technetium-99m tetrofosmin (TF) washout in hypertrophic cardiomyopathy (HCM) was examined by investigating its relation to the metabolic abnormality depicted by iodine-123 beta-methyl- p-iodophenylpentadecanoic acid (BMIPP) uptake and the left ventricular (LV) myocardial wall thickness as measured by magnetic resonance imaging (MRI). TF washout was evaluated in 31 patients with HCM and 23 normal control subjects using 30-min (early) and 3-h (delayed) TF single-photon emission tomography images. The LV myocardial wall was divided into 19 segments and the percentage TF washout, regional BMIPP uptake and LV wall thickness were measured in each segment. Mean TF washout in the patients with HCM was significantly faster than that in normal control subjects (23.7+/-5.7 vs 13.4+/-4.1, P<0.0001). In the patients with HCM, TF washout showed an excellent correlation with MRI wall thickness ( r=0.82, P<0.0001) and a good inverse correlation with regional BMIPP uptake ( r=-0.72, P<0.0001). In addition, a good linear correlation was observed between TF uptake and MRI wall thickness in the 19 regional segments. In conclusion, the degree of TF washout corresponds well with the severity of myocardial wall thickness and the degree of metabolic abnormality in patients with HCM. These results suggest that enhanced TF washout might provide additional clinical information regarding metabolic alterations in HCM.
Eur J Nucl Med Mol Imaging 2003 Jul
PMID:Enhanced washout of 99mTc-tetrofosmin in hypertrophic cardiomyopathy: quantitative comparisons with regional 123I-BMIPP uptake and wall thickness determined by MRI. 1275 3

The large multidomain muscle protein myosin binding protein C (MyBP-C) has been implicated for some time in cardiac disease while until recently little was known about its structure and function. Here we present a detailed study of the central domain C5 of the cardiac isoform of MyBP-C. This domain is unusual in several aspects. Firstly it contains two sizeable insertions compared to the non-cardiac isoforms. The first insertion comprises the linker between domains cC4 and cC5 that is elongated by ten amino acid residues, the second insertion comprises an elongation of the CD-loop in the middle of the domain by approximately 30 amino acid residues. Secondly two point mutations linked to familial hypertrophic cardiomyopathy (FHC) have been identified in this domain. This work shows that the general fold of cC5 is in agreement with the IgI family of beta-sandwich structures. The long cardiac-specific linker between cC4 and cC5 is not a linker at all but an integral part of the fold of cC5, as evidenced by an unfolded mutant in which this segment was removed. The second insertion is shown to be unstructured, highly dynamic and mostly extended according to NMR relaxation measurements and analytical ultracentrifugation. The loss of several key interactions conserved in the CD-loop of the IgI fold is assumed to be responsible for the low stability of cC5 compared to other IgI domains from titin and MyBP-C itself. The low thermodynamic stability of cC5 is most evident in one of the two FHC-linked mutations, N755K (Asn115 in this construct) which is mainly unfolded with a small proportion of a native-like folded species. In contrast, the second FHC-linked mutation, R654H (Arg14 in this construct) is as well folded and stable as the wild-type. This residue is located in the extended beta-bulge at the N terminus of the protein, pointing towards the surface of the CFGA' beta-sheet. This position is in agreement with recent data pointing to a function of Arg654 in an intermolecular interaction with MyBP-C domain cC8.
J Mol Biol 2003 Jun 13
PMID:Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP-C): implications for multidomain assembly and causes for cardiomyopathy. 1278 75

Mutations causing familial hypertrophic cardiomyopathy (HCM) have been described in at least 11 genes encoding cardiac sarcomeric proteins. In this study, three previously unknown deletions have been identified in the human cardiac genes coding for beta-myosin heavy chain (MYH7 on chromosome 14) and myosin-binding protein-C (MYBPC3 on chromosome 11). In family MM, a 3-bp deletion in MYH7 was detected to be associated with loss of glutamic acid in position 927 (DeltaE927) of the myosin rod. In two other families (HH and NP, related by a common founder) a 2-bp loss in codon 453 (exon 16) of MYBPC3 was identified as the presumable cause of a translation reading frame shift. Taken together 15 living mutation carriers were investigated. Six deceased family members (with five cases of premature sudden cardiac death (SCD) in families MM and NP) were either obligate or suspected mutation carriers. In addition to these mutations a 25-bp deletion in intron 32 of MYBPC3 was identified in family MM (five carriers) and in a fourth family (MiR, one HCM patient, three deletion carriers). In agreement with the loss of the regular splicing branch point in the altered intron 32, a splicing deficiency was observed in an exon trapping experiment using MYBPC3 exon 33 as a test substrate. Varying disease profiles assessed using standard clinical, ECG and echocardiographic procedures in conjunction with mutation analysis led to the following conclusions: (1) In family MM the DeltaE927 deletion in MYH7 was assumed to be associated with complete penetrance. Two cases of reported SCD might have been related to this mutation. (2) The two families, HH and NP, distantly related by a common founder, and both suffering from a 2-bp deletion in exon 16 of MYBPC3 differed in their average phenotypes. In family NP, four cases of cardiac death were documented, whereas no cardiac-related death was reported from family HH. These results support the notion that mutations in HCM genes may directly determine disease penetrance and severity; however, a contribution of additional, unidentified factors (genes) to the HCM phenotype can-at least in some cases-not be excluded. (3) The deletion in intron 32 of MYBPC3 was seen in two families, but in both its relation to disease was not unequivocal. In addition, this deletion was observed in 16 of 229 unrelated healthy individuals of the population of the South Indian states of Kerala and Tamil Nadu. It was not seen in 270 Caucasians from Russia and western Europe. Hence, it is considered to represent a regional genetic polymorphism restricted to southern India. The association of the deletion with altered splicing in transfected cells suggests that this deletion may create a "modifying gene", which is per se not or only rarely causing HCM, but which may enhance the phenotype of a mutation responsible for disease.
J Mol Cell Cardiol 2003 Jun
PMID:Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy. 1278 80

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.
J Mol Cell Cardiol 2003 Jul
PMID:Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. 1281 75

An important role of redox regulation in myocardial diseases and heart failure has been postulated. Thioredoxin (TRX) is a redox-regulating protein. Recent studies indicated a possible association between plasma TRX concentrations and the severity of heart failure. Accordingly, we investigated the myocardial expression of TRX in patients with myocarditis and cardiomyopathies. Four cases of hypertrophic cardiomyopathy (HCM), 10 of dilated cardiomyopathy (DCM), 6 of myocarditis, and 5 of controls were studied. Right and left ventricular endomyocardial biopsy samples were obtained at the diagnostic cardiac catheterization. The samples were processed for immunohistological staining for TRX, which was done by the indirect immunoperoxidase technique. 8-hydoxy-2'-deoxyguanosine (8-OHdG), one of the major DNA base-modified products, was also detected for an established marker for oxidative stress. TRX immunoreactivity was none or trivial in control specimens. Positive TRX staining was found in 6 cases; 3 in active myocarditis and 3 in DCM. The positive staining was found in infiltrating cells and damaged myocytes in the perinecrotic lesions. Damaged myocytes were also positive for 8-OHdG All the 3 cases of DCM positive for TRX stain showed severe left ventricular hypertrophy on electrocardiogram and highly elevated left ventricular end-diastolic pressure (> 24 mmHg), suggesting the overload of oxidative stress by hemodynamic impairment. Myocardial TRX was upregulated in myocarditis and cardiomyopathies with active necrotic stage associated with DNA damage, which may reflect the oxidative stress overload in hemodynamically uncontrolled status.
Mol Cell Biochem 2003 Jun
PMID:Upregulation of redox-regulating protein, thioredoxin, in endomyocardial biopsy samples of patients with myocarditis and cardiomyopathies. 1287 Jun 73

Deficiencies in the activity of cytochrome c oxidase (COX) are an important cause of autosomal recessive respiratory chain disorders. Patients with isolated COX deficiency are clinically and genetically heterogeneous, and mutations in several different assembly factors have been found to cause specific clinical phenotypes. Two of the most common clinical presentations, Leigh Syndrome and hypertrophic cardiomyopathy, have so far only been associated with mutations in SURF1 or SCO2 and COX15, respectively. Here we show that expression of COX10 from a retroviral vector complements the COX deficiency in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy. A partial rescue was also obtained following microcell-mediated transfer of mouse chromosomes into patient fibroblasts. COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2. Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme. Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues. A topological model places these residues in regions of the protein shown to have important catalytic functions by mutation analysis of a prokaryotic ortholog. Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy. This study shows that mutations in this gene can cause nearly the full range of clinical phenotypes associated with early onset isolated COX deficiency.
Hum Mol Genet 2003 Oct 15
PMID:Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. 1292 84

Familial hypertrophic cardiomyopathy (HCM) has been defined as a disease of the cardiac sarcomere, although sarcomeric protein mutations are not found in one third of cases. We have recently shown that HCM associated with Wolff-Parkinson-White syndrome (WPW) and conduction disease can be caused by mutations in PRKAG2, which encodes the gamma2 subunit of AMPK, an enzyme central to cellular energy homeostasis. AMPK is a heterotrimer composed of one catalytic subunit (alpha) and two regulatory subunits (beta and gamma). Seven known genes encode the subunit isoforms (alpha1, alpha2, beta1, beta2, gamma1, gamma2, gamma3) and all are expressed in the heart. To better understand the role of AMPK mutations in HCM/WPW and other inherited cardiomyophathies, all 7 subunit genes were screened for mutations in a panel of probands: 3 with HCM/WPW, 4 with DCM/WPW, 38 with HCM alone (in whom contractile protein mutations had not been found) and 13 with DCM alone. In total, 73 amplimers were screened in the 58 probands and a number of polymorphisms, including non-conservative substitutions, were identified. However, no further disease-causing mutations were found in any AMPK subunit gene. These results indicate that HCM with WPW is a distinct, but genetically heterogeneous, condition caused by mutations in PRKAG2 and in an unknown gene or genes, not involved in the AMPK complex. Mutations in PRKAG2 appear to specifically cause HCM with WPW and conduction disease, and not other inherited cardiomyopathies. As deleterious alleles were not found in other AMPK subunit isoforms, the mutations affecting PRKAG2 are likely to confer a specific alteration of AMPK function of particular importance in the myocardium.
J Mol Cell Cardiol 2003 Oct
PMID:Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. 1451 35

A region of interaction between the near N-terminal of cardiac troponin I (cTnI) and the C-lobe of troponin C (cTnC), where troponin T (cTnT) binds, appears to be critical in regulation of myofilament Ca(2+)-activation. We probed whether functional consequences of modulation of this interface influence the function of tropomyosin (Tm) in thin filament activation. We modified the C-lobe of cTnC directly by addition of the Ca(2+)-sensitizer, EMD 57033, and indirectly by replacing native cTnI with cTnI-containing Glu residues at Ser-43 and Ser-45 (cTnI-S43E/S45E) in myofilaments from hearts of non-transgenic (NTG) and transgenic (TG) mice expressing a point mutation on alpha-Tm (E180G) linked to familial hypertrophic cardiomyopathy. Introduction of cTnI-S43E/S45E induced a significantly greater reduction in tension in TG myofilaments compared to NTG controls. Furthermore, the effect of EMD 57033 to restore Ca(2+)-sensitivity was higher in TG compared to NTG fiber bundles containing cTnI-S43E/S45E and compared to TG or NTG fiber bundles containing native TnI. Our results indicate that alterations in regions of interaction among the N-terminal of cTnI, the C-lobe of cTnC, and the C-terminus of cTnT are important in the regulation of myofilament activity. Although levels of phosphorylation at protein kinase C-dependent sites were the same in TG and NTG myofilaments, our data indicate that the effects of phosphorylation were more depressive in TG hearts.
J Mol Cell Cardiol 2003 Oct
PMID:Altered signaling surrounding the C-lobe of cardiac troponin C in myofilaments containing an alpha-tropomyosin mutation linked to familial hypertrophic cardiomyopathy. 1451 38

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in alpha-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.
Mol Genet Metab
PMID:Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. 1578 Dec 1


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