Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ventricular fibrillation leading to sudden cardiac death can occur even in the absence of structural heart disease. One form of this so-called idiopathic ventricular fibrillation (IVF) is characterized by ST segment elevation (STE) in the electrocardiogram. Recently we found that IVF with STE is linked to mutations of SCN5A, the gene encoding the cardiac sodium channel alpha -subunit. Two types of defects were identified: loss-of-function mutations that severely truncate channel proteins and missense mutations (e.g. a double mutation, R1232W and T1620M) that cause only minor changes in channel gating. Here we show that co-expression of the R1232W+T1620M missense mutant alpha -subunits in a mammalian cell line stably transfected with human sodium channel beta(1)-subunits results in a phenotype similar to that of the truncation mutants. In the presence of beta(1)subunits the expression of both ionic currents and alpha -subunit-specific, immunoreactive protein was markedly suppressed after transfection of mutant, but not wild-type alpha -subunits when cells were incubated at physiological temperature. Expression was partially restored by incubation at reduced temperatures. Our results reconcile two classes of IVF mutations and support the notion that a reduction in the amplitude of voltage-gated sodium conductance is the primary cause of IVF.
 ...
PMID:Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation. 1101 31

Sudden cardiac death occurs in the United States with an incidence of more than 300,000 persons per year. The underlying cause of death is commonly considered to be due to primary or secondary arrhythmias. In young persons in whom no structural heart disease can be identified, the long QT syndromes (LQTS) are commonly considered as likely causes. Multiple genes causing LQTS have been identified thus far, all of which encode cardiac ion channels. These include two potassium channel alpha subunits (KVLQT1 and HERG), two potassium channel beta subunits (minK and MiRP1), and one sodium channel gene (SCN5A). The purpose of this review is to describe the current understanding of the molecular genetics of LQTS and the resultant phenotypes, particularly in young patients.
 ...
PMID:Current concepts in long QT syndrome. 1105 Feb 78

We describe a 45-year-old Taiwanese man with specific features of Brugada syndrome but no clinical features of structural heart disease. He was successfully treated with an implantable cardioverter-defibrillator. His electrocardiogram (ECG) patterns changed intermittently. Alpha-adrenoceptor stimulation and beta-adrenoceptor blockade augmented the characteristic ST-segment elevation, whereas alpha-adrenoceptor blockade and beta-adrenoceptor stimulation mitigated the ST-segment elevation. Intravenous procainamide administration did not aggravate ST-segment elevation when ECG had shown coved ST elevation in the right precordial leads. Molecular study did not reveal the same mutations in the cardiac sodium channel gene (SCN5A) as previously reported in Brugada syndrome. This case demonstrates the genetic heterogeneity of SCN5A in Brugada syndrome.
 ...
PMID:Brugada syndrome without mutation of the cardiac sodium channel gene in a Taiwanese patient. 1115 78

Sudden cardiac death occurs in the United States with an incidence greater than 300,000 persons per year. The underlying cause of death is commonly considered to be due to primary or secondary arrhythmias. In cases in which no structural heart disease can be identified, the long QT syndromes (LQTS) are now commonly considered as likely causes. Multiple genes causing LQTS have been identified thus far, all encoding cardiac ion channels. These include two potassium channel alpha-subunits (KVLQT1, HERG), two potassium channel beta-subunits (minK, MiRP1), and one sodium channel gene (SCN5A). The purpose of this review is to describe the current understanding of the molecular genetics of LQTS and the resultant phenotypes.
 ...
PMID:Genotype and severity of long QT syndrome. 1125 55

The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator.
 ...
PMID:The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities. 1134 71

Brugada syndrome is an inherited cardiac disorder caused by mutations in the cardiac sodium channel gene, SCN5A, that leads to ventricular fibrillation and sudden death. This study reports the changes in functional expression and cellular localization of an SCN5A double mutant (R1232W/T1620M) recently discovered in patients with Brugada syndrome. Mutant and wild-type (WT) human heart sodium channels (hNa(v)1.5) were expressed in tsA201 cells in the presence of the beta(1)-auxiliary subunit. Patch-clamp experiments in whole-cell configuration were conducted to assess functional expression. Immunohistochemistry and confocal microscopy were used to determine the spatial distribution of either WT or mutant cardiac sodium channels. The results show an abolition of functional sodium channel expression of the hNa(v)1.5/R1232W/T1620M mutant in the tsA201 cells. A conservative positively charged mutant, hNa(v)1.5/R1232K/T1620M, produced functional channels. Immunofluorescent staining showed that the FLAG-tagged hNa(v)1.5/WT transfected into tsA201 cells was localized on the cell surface, whereas the FLAG-tagged hNa(v)1.5/R1232W/T1620M mutant was colocalized with calnexin within the endoplasmic reticulum (ER). These results indicate that a positively charged arginine or lysine residue at position 1232 in the double mutant is required for the proper transport and functional expression of the hNa(v)1.5 protein. These results support the concept that loss of function of the cardiac Na(+) channel is responsible for the Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
 ...
PMID:Expression and intracellular localization of an SCN5A double mutant R1232W/T1620M implicated in Brugada syndrome. 1178 29

The long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs), syncope and sudden death caused by a specific ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in ion channel genes including the cardiac sodium channel gene SCN5A, and potassium channel subunit genes KCNQ1, KCNH2, KCNE1, and KCNE2. Little information is available about LQTS mutations in the Chinese population. In this study, we characterized 42 Chinese LQTS families for mutations in the two most common LQTS genes, KCNQ1 and KCNH2. We report here the identification of four novel KCNQ1 mutations and three novel KCNH2 mutations. The KCNQ1 mutations include L191P in the S2-S3 cytoplasmic loop, F275S and S277L in the S5 transmembrane domain, and G306V in the channel pore. The KCNH2 mutations include L413P in transmembrane domain S1, E444D in the extracellular loop between S1 and S2, and L559H in domain S5. The location and character of these mutations expand the spectrum of KCNQ1 and KCNH2 mutations causing LQTS. Excitement, exercises, and stress appear to be the triggers for developing cardiac events (syncope, sudden death) for LQTS patients with KCNQ1 mutations F275S, S277L, and G306V, and all three KCNH2 mutations L413P, E444D and L559H. In contrast, cardiac events for an LQTS patient with KCNQ1 mutation L191P occurred during sleep or awakening from sleep. KCNH2 mutations L413P and L559H are associated with the bifid T waves on ECGs. Inderal or propanolol (a beta blocker) appears to be effective in preventing arrhythmias and syncope for an LQTS patient with the KCNQ1 L191P mutation.
 ...
PMID:KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. 1244 76

The flecainide test is widely used in Brugada syndrome. However, its reproducibility and safety remain ill-defined. This study included 22 patients (18 men, mean age 34 years). Mutations in the SCN5A gene were found in eight patients. Two patients had aborted sudden cardiac death, 8 had syncope/presyncope, and 12 were asymptomatic. The ECG was diagnostic in 19 patients and suggestive in 3. At baseline, 21 of 22 patients underwent a flecainide test (2 mg/kg IV bolus over 10 minutes). In 21 of 21 patients the test was diagnostic or amplified the typical ECG pattern. At the end of drug infusion, sustained VT lasting 7-10 minutes developed in two patients. A second flecainide test was performed within 2 months in 20 patients. The test was not repeated in the two patients with prior development of VT. The flecainide test was diagnostic in 20 of 20 patients. Sustained VT occurred in one patient and recurrent VF in another. The reproducibility of the flecainide test was 100%. In 4 (18%) of 22 patients major VAs were documented after the end of flecainide infusion. VA occurred in 3 (43%) of 7 patients with, versus 1 (7%) 15 without SCN5A gene mutation (P < 0.05). No diagnostic ECG changes or arrhythmias developed in 25 control patients without structural heart disease who underwent the same study protocol. This study shows a high flecainide reproducibility, supporting its diagnostic value in Brugada syndrome. However, the occurrence of major VA, significantly higher in patients with documented SCN5A gene mutation, including in asymptomatic patients, mandates the performance under appropriate medical supervision. Whether a slower rate of drug infusion can lower the risk of VA induction, while maintaining the sensitivity of the test should be explored.
 ...
PMID:Flecainide test in Brugada syndrome: a reproducible but risky tool. 1268 41

Febrile illness has been rarely reported to modulate ST segment elevation in right precordial leads on ECG or even precipitate ventricular fibrillation in patients with Brugada syndrome. We report the case of a patient whose Brugada ECG pattern was unmasked by hyperthermia secondary to acute cholangitis. Serial ECGs showed progressive attenuation of ST segment elevation as body temperature gradually returned to normal. Structural heart disease was ruled out. Intravenous flecainide injection reproduced a less remarkable ST segment elevation. Genetic screening demonstrated a single amino acid substitution (H681P) in the SCN5A gene, thus confirming the diagnosis of Brugada syndrome. In vitro expression of this newly characterized genetic defect revealed novel biophysical abnormalities consisting of a shift in both steady-state activation and inactivation, resulting in a 60% reduction of sodium window current. Thus, SCN5A-H681P mutation induces a significant loss of transmembrane current and is clinically associated with a pathologic phenotype that is elicited by hyperthermia. Overall the observed clinical features are in agreement with previous observations and strongly suggest that fever may be an environmental modifier among Brugada syndrome patients with a detrimental (and possibly arrhythmogenic) effect on cardiac repolarization.
 ...
PMID:A newly characterized SCN5A mutation underlying Brugada syndrome unmasked by hyperthermia. 1467 48

Amino acid sequence variations in SCN5A are known to affect function of wild-type channels and also those with coexisting mutations; therefore, it is important to know the exact sequence and function of channels most commonly present in human myocardium. SCN5A was analyzed in control panels of human alleles, demonstrating that the existing clones (hH1, hH1a, hH1b) each contained a rare variant and thus none represented the common sequence. Confirming prior work, the H558R polymorphism was present in approximately 30% of subjects. Quantitative mRNA analysis from human hearts showed that a shorter 2015 amino acid splice variant lacking glutamine at position 1077 (Q1077del) made up 65% of the transcript in every heart examined. Age, sex, race, or structural heart disease did not affect this proportion of Q1077del. Estimated population frequencies for the four common variants were 25% SCN5A, 10% [H558R], 45% [Q1077del], and 20% [H558R;Q1077del], where the reference sequence SCN5A is GenBank AC137587. When expressed in HEK-293 cells, these common variants had a more positive mid-point of the voltage dependence of inactivation than the standard clone hH1. Also, channels containing Q1077 expressed smaller currents. When H558R was present with Q1077 ([H558R]), current expression was profoundly reduced despite normal trafficking to the cell surface. Thus, four variant sequences for SCN5A are commonly present in human myocardium and they exhibit functional differences among themselves and with the previous standard clone. These results have implications for the choice of background sequence for experiments with heterologous expression systems, and possibly implications for electrophysiological function in vivo.
 ...
PMID:A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels. 1450 Mar 39


<< Previous 1 2 3 4 5 6 Next >>