Gene/Protein Disease Symptom Drug Enzyme Compound
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Familial hypertrophic cardiomyopathy is an autosomal dominant genetically heterogeneous disease characterized by a partial penetrance and variable expressivity. Previous studies showed that the extent of hypertrophy is influenced by the angiotensin I converting enzyme insertion/deletion (I/D) polymorphism. Recently, molecular genetic analysis revealed the existence of healthy carriers and that as many as a quarter of genetically affected individuals do not express the disease. This data prompted us to re-investigate the role of the angiotensin I converting enzyme polymorphism on hypertrophy by assessing both clinically affected individuals and healthy carriers. For this, several families with mutations in the cardiac myosin binding protein C or the beta-myosin heavy chain genes were analysed. The mean maximal intraventricular septum thickness was compared as a function of angiotensin I converting enzyme genotypes in all genetically affected individuals (n = 114), and in subsets of subjects carrying either a splice acceptor site mutation in the cardiac myosin binding protein C gene (n = 33), or various missense mutations in the cardiac beta-myosin heavy chain gene (n = 81) or finally, mutation in the Arg403 codon of the beta-myosin heavy chain gene (n = 54). Significant association between the D allele and hypertrophy was observed only in the case of Arg403 codon mutations (mean septum thickness for subjects with the DD genotype: 19.3 +/- 2.7 mm: with the ID genotype: 13.4 +/- 1.3 mm and with the II genotype: 11.0 +/- 0.9 mm; P < 0.02). These results were confirmed by the chi 2 test showing an over-representation of DD genotype in patients carrying an Arg403 codon mutation associated with septal hypertrophy (P < 0.05). Our data confirms that the angiotensin I converting enzyme genotypes can influence the phenotypic expression of hypertrophy and shows that this influence depends on the mutation, raising the concept of multiple genetic modifiers in familial hypertrophic cardiomyopathy.
J Mol Cell Cardiol 1997 Feb
PMID:The influence of the angiotensin I converting enzyme genotype in familial hypertrophic cardiomyopathy varies with the disease gene mutation. 914 Aug 39

Familial hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy with an autosomal dominant pattern of inheritance. The disease bearing genes for HCM in HCM families have been identified as beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin T (cTnT) and myosin binding protein-C genes. In the present study, we searched for the mutations in the cTnT gene in Japanese HCM patients. Single-strand conformation polymorphism gel analysis of polymerase chain reaction-amplified product was used to search for the mutations in the exons 8, 9 and 15 of the cTnT gene from 60 familial HCM patients. Clinical studies of the family members were performed and the incidence of sudden or disease-related deaths within the family was also examined. We have identified a novel missense mutation in exon 9 (Ala104Val) of the cTnT gene in a patient with familial HCM. Because the missense mutation was found at the residue conserved through chicken to humans and was not detected in the more than 50 normal controls, it was suggested that this missense mutation is the cause of HCM in this family. Although the affected family members presented moderate hypertrophy of the left ventricular wall, they were symptomatic and there was a high incidence of sudden death in her family members. Among Japanese patients with familial HCM, a novel missense mutation (Ala104Val) in the cTnT gene was identified. Familial HCM is genetically heterogeneous in Japanese HCM patients as observed in Caucasian kindreds. The disease in the kindred was severe and there was a high incidence of sudden or disease-related deaths in the kindred with this mutation.
J Mol Cell Cardiol 1997 Feb
PMID:Novel missense mutation in cardiac troponin T gene found in Japanese patient with hypertrophic cardiomyopathy. 914 Aug 40

Mitochondrial trifunctional protein (TP), an enzyme of beta-oxidation, is a multienzyme complex composed of four molecules of the alpha-subunit (HADHA) containing the enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase domains and four molecules of the beta-subunit (HADHB) containing the 3-ketoacyl-CoA thiolase domain. An inborn error of this enzyme complex can cause sudden infant death syndrome, acute hepatic encephalopathy or liver failure, skeletal myopathy, or hypertrophic cardiomyopathy. TP deficiency is classified into two different biochemical phenotypes: one represents the existence of both subunits and the lack of only the 3-hydroxyacyl-CoA dehydrogenase activity and the other represents the absence of both subunits and the lack of all three TP activities, although their clinical features are similar. We have identified two Japanese patients with this disorder. Three enzyme activities of TP were undetectable in fibroblasts from these two patients. We detected two mutations in the HADHB gene from two Japanese patients, an exonic single T insertion which created a new cryptic 5' splice site and a G1331A transition (R411 K). Patient 1 was a compound heterozygote, while patient 2 was a homozygote of a G1331A transition.
Hum Mol Genet 1997 Aug
PMID:Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. 925 66

Hypertrophic cardiomyopathy (HCM) is manifested by severe thickening of the left ventricle with significant diastolic dysfunction. Previous observations on the improvement in diastolic function and left ventricular wall thickness through the therapeutic administration of coenzyme Q10 (CoQ10) in patients with hypertensive heart disease prompted the investigation of its utility in HCM. Seven patients with HCM, six non-obstructive and one obstructive, were treated with an average of 200 mg/day of CoQ10 with mean treatment whole blood CoQ10 level of 2.9 micrograms/ml. Echocardiograms were obtained in all seven patients at baseline and again 3 or more months post-treatment. All patients noted improvement in symptoms of fatigue and dyspnea with no side effects noted. The mean interventricular septal thickness improved significantly from 1.51 +/- 0.17 cm to 1.14 +/- 0.13 cm, a 24% reduction (P < 0.002). The mean posterior wall thickness improved significantly from 1.37 +/- 0.13 cm to 1.01 +/- 0.15 cm, a 26% reduction (P < 0.005). Mitral valve inflow slope by pulsed wave Doppler (EF slope) showed a non-significant trend towards improvement, 1.55 +/- 0.49 m/sec2 to 2.58 +/- 1.18 m/sec2 (P < 0.08). The one patient with subaortic obstruction showed an improvement in resting pressure gradient after CoQ10 treatment (70 mmHg to 30 mmHg).
Mol Aspects Med 1997
PMID:Treatment of hypertrophic cardiomyopathy with coenzyme Q10. 926 16

In order to investigate differences in the pathophysiology of cardiac hypertrophy between patients with arterial hypertension and hypertrophic cardiomyopathy, DNA synthesis by cardiac myocytes and the effects of an angiotensin-converting enzyme inhibitor were examined in these two groups of patients. DNA synthesis and the cell cycle were investigated by flow cytometry using autopsy materials from patients with hypertension and hypertrophic cardiomyopathy. The hypertension group (n=10) included four men and six women aged 61+/-10 years (heart weight: 470+/-79 g, mean+/-s.d.); the cardiomyopathic group (n=10) included eight men and two women aged 61+/-23 years (heart weight: 615+/-211 g). The percentage of cells in G2M phase of the cell cycle was significantly decreased in the myocardium from patients with hypertrophic cardiomyopathy compared with that from hypertensive patients (cardiomyopathy v hypertension: 1.1+/-0.6 v 7.7+/-2.6%, mean+/-s.d.). Captopril, an angiotensin-converting enzyme inhibitor, was administered for 12 months to patients with hypertension (n=20) and hypertrophic cardiomyopathy (n=15). Regression of cardiac hypertrophy was assessed by echocardiography. Long-term administration of captopril achieved regression of cardiac hypertrophy in the hypertensive patients, but not in the patients with hypertrophic cardiomyopathy. In the hypertensive patients, the left ventricular mass was 234+/-9 g before treatment and 198+/-26 g after treatment (mean+/-s.d., P<0. 01). In cardiomyopathic patients, on the other hand, there was no significant difference of left ventricular mass after treatment (before v after, 305+/-85 v 285+/-90 g, mean+/-s.d.). These results suggest that the mechanism of cardiac hypertrophy differs between patients with hypertension and hypertrophic cardiomyopathy.
J Mol Cell Cardiol 1997 Nov
PMID:Different pathophysiology of cardiac hypertrophy in hypertension and hypertrophic cardiomyopathy. 940 71

Our former studies concerning mitochondrial DNA mutations were reviewed in this article. A 7.4 kb deletion between the D-loop and ATPase 6 genes was detected in myocardial tissue obtained at autopsy from patients with myocardial infarction, diabetes mellitus and also patients treated with adriamycin. A case with diabetes mellitus and hypertrophic cardiomyopathy is demonstrated which revealed a point mutation from adenine to guanine at position 3243 within tRNA Leu(UUR).
Mol Cell Biochem 1997 Nov
PMID:Cardiomyopathies and mitochondrial DNA mutations. 940 74

We have recently developed a porcine model with naturally occurring hypertrophic cardiomyopathy (HCM). Similar to humans, occluded intramural coronary artery and damaged mitochondria are frequently observed in these animals in which the disease is thought to be associated with the local ischemia of myocardium. In view of antioxidant functions involved in the ischemic injury, we measured the expression of endogenous antioxidant enzymes in the tissues with and without HCM. The results showed a significant increase of Cu,Zn-superoxide dismutase (SOD), but not Mn-SOD, and decrease of catalase (CAT) activities in the various areas of HCM hearts. It was demonstrated that SOD/CAT ratios in the HCM hearts were significantly higher than those in normals and were found to be dramatically correlated with the severity of cardiac hypertrophy. The altered SOD/CAT ratio was also consistent with increase in lipid damage. We hypothesize that the elevated SOD combined with an inadequate amount of H2O2 scavenging enzyme may lead HCM heart at oxidative stress risk. However, the pathogenic role of imbalanced antioxidant enzyme needs to be further explored.
Biochem Mol Biol Int 1997 Dec
PMID:Alteration of endogenous antioxidant enzymes in naturally occurring hypertrophic cardiomyopathy. 944 21

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.
J Mol Med (Berl) 1998 Mar
PMID:Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. 953 54

Mutations in the cardiac beta -myosin heavy chain gene (MYH7), and other genes encoding cardiac sarcomere proteins may cause familial hypertrophic cardiomyopathy (F-HCM), an autosomal dominant disease, characterized by myocardial hypertrophy. We analysed the MYH7 gene in three generations of a family with one borderline and four clinically verified cases of hypertrophic cardiomyopathy, and identified a mutation in exon 7 changing the 190 arginine residue into a threonine residue. The mutation is located in the ATP-binding region of the myosin head and alters the charge in the F-helix close to the phosphate-binding P-loop. The mutation may thus interfere with the coupling between ATP-hydrolysis and the transition into mechanical energy. In conclusion, the novel Arg190Thr mutation in exon 7 of the MYH7 gene is associated with the development of symptomatic myocardial hypertrophy in adults.
J Mol Cell Cardiol 1999 Apr
PMID:Familial hypertrophic cardiomyopathy associated with a novel missense mutation affecting the ATP-binding region of the cardiac beta-myosin heavy chain. 1032 2

CD36 is homologous with myocardial long-chain fatty acid (LCFA) binding protein and has been suggested to relate to myocardial fatty acid metabolism. Myocardial scintigraphy with iodine-123 15-(p-iodophenyl)-3-(R, S)-methylpentadecanoic acid (BMIPP) revealed an impairment in LCFA metabolism chiefly in the hypertrophic myocardium in hypertrophic cardiomyopathy (HCM). Recently, the incidence of CD36 deficiency has been reported to be high in HCM patients, and CD36 deficiency was proposed as an etiology of hereditary HCM. However, the pathophysiological effect of CD36 deficiency on HCM has not been fully investigated. We analysed the expression of CD36 antigens on both platelets and monocytes obtained from 82 patients with HCM using two-color flow cytometry. Among the study patients, seven patients (8.5%) demonstrated type II CD36 deficiency, whereas type I CD36 deficiency was not detected. Two of 23 patients (8.7%) with a family history of HCM and five of 59 patients (8.5%) without a family history of HCM showed type II CD36 deficiency respectively. Contrary to the previous report, three of 53 patients with asymmetric septal hypertrophy (ASH) (5.7%) and four of 29 patients without ASH (13.8%) showed CD36 deficiency. Moreover, clinical characteristics, scintigraphic findings, echocardiographic data, and hemodynamic findings disclosed no significant differences between the HCM patients showing normal CD36 expression and those with CD36 deficiency. The incidence of CD36 deficiency in HCM patients is not higher than in the general population. Therefore, CD36 deficiency is not a characteristic factor of HCM and has little influence on the pathyphysiology of HCM.
J Mol Cell Cardiol 1999 Jun
PMID:CD36 deficiency has little influence on the pathophysiology of hypertrophic cardiomyopathy. 1037 99


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