Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0018799 (heart disease)
34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rapid progress in the isolation of genes associated with human disease has resulted in an increasing demand for mutation screening methods. The molecular diagnosis of the long QT syndrome (LQTS), a cardiac disorder characterized by prolongation of the QT(c) interval in the ECG, syncopes, and sudden death, requires mutation screening of all exons in at least five genes, encoding cardiac Na(+) and K(+) channel subunits. A method for automated dideoxy fingerprinting (ddF) using capillary array electrophoresis (CAE) was developed and the efficiency of the method was tested by analyzing 24 DNA samples with mutations in one of the genes KCNQ1 and KCNH2, which are involved in 50% of LQTS cases. One of these mutations, 362insQK in KCNQ1, is novel. The sensitivity was 100% using a single electrophoresis temperature of 18 degrees C or 25 degrees C. However, analysis of the samples in both the sense and anti-sense direction were required for high sensitivity. Analysis in a single direction resulted in a decrease of the sensitivity to 74% and 70%, respectively. The throughput of the ddF method, if performed with a 16 capillary CAE instrument, is 288 samples per seven hr if each sample is analyzed on both strands.
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PMID:Automated mutation screening using dideoxy fingerprinting and capillary array electrophoresis. 1166 38

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.
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PMID:KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. 1244 76

Multiple mutations in several ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2) have been shown to cause autosomal dominant long QT syndrome (LQTS), a familial cardiac disorder that causes syncope, seizures, and sudden death. Due to their multiple loci and considerable size, mutation detection in these genes represents a challenge that is only partially met by the conventional screening method of single-stranded conformational polymorphism (SSCP). The recently introduced denaturing high-performance liquid chromatography (dHPLC) offers a promising new method for a fast and sensitive analysis of PCR-amplified DNA fragments. To test the applicability of dHPLC in the molecular diagnosis of LQTS, we first assessed a cohort of 192 patients from our International LQTS Registry for 14 previously identified mutations (including 10 different missense mutations, 1-bp, 2-bp, 3-bp, and 9-bp deletion mutations), and 2 polymorphisms in the LQTS potassium and sodium channel genes. Applying empirically determined exon-specific melting profiles, all mutations (including four previously undetectable by SSCP) were readily identified by dHPLC. We conclude that the dHPLC technology is a highly sensitive and efficient method for the molecular analysis of LQTS, and the same PCR amplicons developed for SSCP testing can be directly used for dHPLC assay.
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PMID:Denaturing high-performance liquid chromatography quickly and reliably detects cardiac ion channel mutations in long QT syndrome. 1464 2

LQTS (long QT syndrome) is an inherited cardiac disorder characterized by prolongation of QT interval, torsades de pointes and sudden death. We have identified two heterozygous missense mutations in the KCNQ1 and KCNH2 (also known as HERG) genes [Asp611-->Tyr (D611Y) in KCNQ1 and Asp609-->Gly (D609G) in KCNH2] in a 2-year-old boy with LQTS. The aim of the present study was to characterize the contributions of the mutations in the KCNQ1 and KCNH2 genes relative to the clinical manifestations and electrophysiological properties of LQTS. Six of 11 carriers of D611Y in KCNQ1 had long QT intervals. D609G in KCNH2 was detected only in the proband. Studies on the electrophysiological alterations due to the two missense mutations revealed that the D611Y mutation in KCNQ1 did not show a significant suppression of the currents compared with wild-type, but the time constants of current activation in the mutants were increased compared with that in the wild-type. In contrast, the D609G mutation in KCNH2 showed a dominant-negative suppression. Our results suggest that the mild phenotype produced by the D611Y mutation in KCNQ1 became more serious by addition of the D609G mutation in KCNH2 in the proband.
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PMID:Compound heterozygosity for mutations Asp611-->Tyr in KCNQ1 and Asp609-->Gly in KCNH2 associated with severe long QT syndrome. 1550 Apr 50

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The term lone AF describes nonsyndromic atrial fibrillation that occurs in the absence of underlying structural heart disease or predisposing clinical conditions. A hereditable component leading to conduction abnormalities in AF has long been suspected, and epidemiological evidence of elevated risk for AF among first-degree relatives of probands was recently documented. The first AF-associated molecular defect was found in an affected Chinese family; initial studies narrowed the chromosomal location by linkage analysis, and Yihan Chen et al. found a specific gain-of-function mutation in KCNQ1, the gene for the alpha subunit of potassium channels.
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PMID:Gene mutations, atrial fibrillation, and the elusive cigar. 1718 97

The long-QT syndrome (LQTS) is an inherited cardiac disorder associated with syncope and a high risk of sudden death. The molecular basis of type-1 LQTS (LQT1) is a missense or nonsense mutation in KCNQ channels that reduces slowly activating delayed rectifier potassium channel (I(Ks)) resulting in a prolonged action potential. Noticeably, the S2-S3 linker is a highly congregating region of LQT1 mutations. To further explore the mechanism, a KCNQ mutant (L191P) identified in one Chinese pedigree with LQT1 was chosen for this purpose. As Leu-191 is located in the middle of a well-known endoplasmic reticulum (ER) localization signal (RXR) in the intracellular S2-S3 linker, we examined the kinetics and the surface expression of both the KCNQ1 and L191 mutants. Our results showed that the mutation did not affect the channel kinetics, whereas the surface expression increased with increasing hydrophobicity of the middle residue 'X' of the RXR motif. Based on an analysis of fractional fluorescence data using a binomial model, we also found that the percentage of KCNQ1/L191P heteromeric channels expressed at the cell surface were 22.0%, 40.5%, 27.9%, 8.6% and 1.0% of heteromeric channels with 0, 1, 2, 3 and 4 subunits of L191P, respectively, in a transfected ratio of KCNQ1: L191P=1:1. These experiments demonstrated that coexpression of L191P resulted in a trafficking factor alpha<1, causing a trafficking deficiency of heteromeric channels that underlay the dominant-negative effect. This study suggests several trafficking signals coexisting in this region, and expands our understanding of possible dominant-negative mechanisms underlying LQTS.
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PMID:A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel. 1904 15

Congenital long QT syndrome is a cardiac disorder characterized by prolongation of QT interval on the surface ECG associated with syncopal attacks and a high risk of sudden death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of long QT syndrome (LQT1). We previously identified a hot spot mutation G314S located within the pore region of the KCNQ1 ion channel in a Chinese family with long QT syndrome. In the present study, we used oocyte expression of the KCNQ1 polypeptide to study the effects of the G314S mutation on channel properties. The results of electrophysiological studies indicate G314S, co-expressed with KCNE1 was unable to assemble to form active channel. G314S, co-expressed with WT KCNQ1 and KCNE1, suppressed I(ks) currents in a dominant-negative manner, which is consistent with long QT syndrome in the members of the Chinese family carrying G314S KCNQ1 mutation.
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PMID:The G314S KCNQ1 mutation exerts a dominant-negative effect on expression of KCNQ1 channels in oocytes. 1934 85

The long QT syndrome (LQTS) is a cardiac disorder caused by a prolonged ventricular repolarization. The co-assembly of the pore-forming human KCNQ1 alpha-subunits with the modulating hKCNE1 beta-subunits generates I(Ks)in vivo, explaining why mutations in the hKCNQ1 gene underlie the LQT1 form of congenital LQT. Here we describe the functional defects of the LQT1 mutation H258R located in the S4-S5 linker, a segment important for channel gating. Mutant subunits with this arginine substitution generated no or barely detectable currents in a homotetrameric condition, but did generate I(Ks)-like currents in association with hKCNE1. Compared to the WT hKCNQ1/hKCNE1 complex, the H258R/hKCNE1 complex displayed accelerated activation kinetics, slowed channel closure and a hyperpolarizing shift of the voltage-dependence of activation, thus predicting an increased K(+) current. However, current density analysis combined with subcellular localization indicated that the H258R subunit exerted a dominant negative effect on channel trafficking to the plasma membrane. The co-expression hKCNQ1/H258R/hKCNE1, mimicking the heterozygous state of a patient, displayed similar properties. During repetitive stimulation the mutant yielded more current compared to WT at 1 Hz but this effect was counteracted by the trafficking defect at faster frequencies. These rate-dependent effects may be relevant given the larger contribution of I(Ks) to the "repolarization reserve" at higher action potential rates. The combination of complex kinetics that counteract the trafficking problem represents a particular mechanism underlying LQT1.
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PMID:The rate-dependent biophysical properties of the LQT1 H258R mutant are counteracted by a dominant negative effect on channel trafficking. 1991 47

Congenital long QT syndrome is an inherited cardiac disorder characterized by a prolonged QT interval and polymorphic ventricular arrhythmias that could result in recurrent syncope, seizures or sudden death as the most dramatic event. Until now QT interval mutations have been described in 12 genes, where the majority of mutations reside in three genes KCNQ1, KCNH2, and SCN5A. Diagnosis and prognosis are directly related with the gene and mutation involved. We have developed a diagnostic approach for long QT syndrome and Brugada syndrome based on published mutations and Sequenom MassArray system. Three diagnostic tests have been developed, oriented to each of the three most prevalent genes in the long QT syndrome. A total of 433 mutations are analyzed in 38 multiplex reactions, allowing their detection in about 48 h. Tests were validated on 502 samples from individuals with different clinical conditions and family history. The average call rates obtained for each of the tests were 93, 83, and 73% in KCNQ1, KCNH2, and SCNA, respectively. Sequenom MassARRAY mutation detection is a reliable, highly flexible, and cost-efficient alternative to conventional methods for genetic testing in long QT syndrome and Brugada syndrome, facilitating flexible upgrades of the version of the test presented here with the inclusion of new mutations.
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PMID:A new approach to long QT syndrome mutation detection by Sequenom MassARRAY system. 2048 26

Long QT syndrome (LQTS) is a cardiac disorder associated with sudden death especially in young, seemingly healthy individuals. It is characterised by abnormalities of the heart beat detected as lengthening of the QT interval during cardiac repolarisation. The incidence of LQTS is given as 1 in 2000 but this may be an underestimation as many cases go undiagnosed, due to the rarity of the condition and the wide spectrum of symptoms. Presently 12 genes associated with LQTS have been identified with differing signs and symptoms, depending on the locus involved. The majority of cases have mutations in the KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes. Genetic testing is increasingly used when a clearly affected proband has been identified, to determine the nature of the mutation in that family. Unfortunately tests on probands may be uninformative, especially if the defect does not lie in the set of genes which are routinely tested. Novel mutations in these known LQTS genes and additional candidate genes are still being discovered. The functional implications of these novel mutations need to be assessed before they can be accepted as being responsible for LQTS. Known epigenetic modification affecting KCNQ1 gene expression may also be involved in phenotypic variability of LQTS. Genetic diagnosis of LQTS is thus challenging. However, where a disease associated mutation is identified, molecular diagnosis can be important in guiding therapy, in family testing and in determining the cause of sudden cardiac death. New developments in technology and understanding offer increasing hope to families with this condition.
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PMID:Molecular genetics of long QT syndrome. 2059 83


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