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)

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
Hum Mol Genet 1995 Sep
PMID:Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. 854 46

In the long QT syndrome, excessive prolongation of the cardiac action potential leads to polymorphic ventricular tachycardia (torsades de pointes) and sudden death. Mutations in HERG have been identified as one of the causes of the chromosome 7-linked form of congenital long QT syndrome. The biophysical properties of currents recorded from HERG expressing Xenopus oocytes are similar to those of a cardiac K+ current, I(Kr), but the characteristic nanomolar methanesulfonanilide sensitivity has not been demonstrated. To determine the biophysical and pharmacological properties of HERG under experimental conditions similar to those used to study native cardiac currents, we examined currents expressed after expression of HERG in a human cell line, human embryonic kidney 293. Transfected cells display K+-selective outward currents that activated at membrane potentials positive to -50 mV with strongly voltage-dependent kinetics [time constant (tau) = 2 sec at -20 mV and 188 msec at +20 mV]. Marked inward rectification was observed for depolarizations positive to +0 mV, which was due to rapid channel inactivation (tau = 6 msec at +50 mV). The subsequent tail currents at -40 mV displayed an initial rising phase with tau = 10 msec, followed by a slow multiexponential decline. The EC50 for the methanesulfonanilide I(Kr) blocker dofetilide was 12 +/- 2 nM. Induction of block depended on depolarization beyond the threshold for channel opening. Time-dependent block developed slowly, with tau = 5.2 +/- 0.6 sec (300 nM) at +10 mV, and was delayed by stronger depolarizations. This pattern suggested that dofetilide preferentially blocks open (or activated) channels and that the fast inactivation may competitively slow the binding kinetics. The latter occurrence was further supported by a simplified mathematical model that addressed the impact on binding kinetics of fast inactivation. These results indicate that the HERG gene product encodes an alpha subunit that, when expressed in mammalian cells, displays both the major functional and pharmacological properties of native I(Kr). Dofetilide acts as a slow-onset/slow-offset open channel blocker of this current at nanomolar concentrations.
Mol Pharmacol 1996 Jun
PMID:High affinity open channel block by dofetilide of HERG expressed in a human cell line. 864 54

Patients with long QT syndrome (LQTS; MIM 1921500) frequently suffer from syncope and are threatened by sudden cardiac death due to ventricular arrhythmias, typically of the torsade de pointes type. Initial progress in revealing the molecular basis of the disease was made by the observation of genetic linkage of the disease locus to the Harvey Ras-1 gene (HRAS 1) on chromosome 11p15.5. More recently loci on chromosomes 3, 4, and 7 have also been found to be linked to LQTS, thus demonstrating heterogeneity in the causes for this disease. The present study performed sequence analysis on the HRAS 1 gene in patients with congenital and acquired LQTS to determine the frequency of HRAS 1 mutations in patients with this disease. In neither group were no mutations identified in the coding regions or in the splice donor and acceptor sites. Alleles characterized by a T to C transition in exon 1 and an insertion/deletion polymorphism upstream of exon 1 showed no significant difference in their frequencies between LQTS patients and normal controls. No quantitative influence of the such characterized genotypes on the QT duration was observed. These results demonstrate that structural mutations in the HRAS 1 gene are not a frequent cause of LQTS. Also, since there was no association of different alleles at the HRAS 1 locus with changes in QT duration, it appears unlikely that this gene is a major contributor to this disease.
J Mol Med (Berl) 1995 Nov
PMID:Molecular analysis at the Harvey Ras-1 gene in patients with long QT syndrome. 875 Nov 40

Congenital long QT syndrome (LQTS) is a heterogeneous group of heritable disorders characterized by prolongation of the QT interval on the electrocardiogram, ventricular arrhythmias and sudden death. At least four genes can, when mutated, produce this phenotype. Of these genes, the recently identified KVLQT1 potassium channel is thought to be the one most commonly responsible. In this study, we used single strand conformational polymorphism (SSCP) analysis to screen two large and nine small LQTS families for mutations of the KVLQT1 potassium channel gene. We identified a novel missense mutation in two unrelated families which substitutes a serine for a conserved glycine in the putative pore region of the KVLQT1 channel. In a third family, a new alanine to valine mutation at a CpG dinucleotide resulted in the spontaneous occurrence of the long QT syndrome in monozygotic twin offspring of unaffected parents. Mutations at this same nucleotide have been observed in eight of the 19 LQTS families determined to have KVLQT1 mutations, suggesting this is a mutational hot spot. Both of these mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and many diminish the channel's ability to conduct a repolarizing potassium current. To date, all KVLQT1 mutations determined to cause the LQTS are missense mutations. These data confirm the role of KVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert a dominant negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully-functional KVLQT1 channels.
Hum Mol Genet 1996 Sep
PMID:KVLQT1 mutations in three families with familial or sporadic long QT syndrome. 887 72

Long QT syndrome (LQT) is a genetically heterogeneous inherited disorder that causes sudden death from cardiac arrhythmia. Four loci have been mapped to chromosomes 3, 4, 7 and 11 and three specific mutated genes for LQT syndrome have been identified. LQT2 results from mutations in the human ether-a-gogo-related gene, HERG, a cardiac potassium channel, whose protein product likely underlies Ikd the rapidly activating delayed rectifier current. By SSCP analysis and direct sequencing, we determined a new missense mutation in the HERG coding sequence, a G to A transition at position 1681 resulting in the substitution of threonine for a highly conserved alanine at codon 561. This mutation, Ala561Thr, in the coding sequence of the fifth membrane-spanning domain (S5) of the HERG protein seems to convey a risk of cardiac events in affected family members. In addition to a prolonged T wave of low amplitude on the surface ECG, a distinctive biphasic T-wave pattern was found in the left precordial leads of all affected subjects with the Ala561Thr mutation regardless of age, gender and beta blocking therapy.
J Mol Cell Cardiol 1996 Aug
PMID:A mutation in HERG associated with notched T waves in long QT syndrome. 887 71

Ion channels are part of a large family of macromolecules whose functions include the control and maintenance of electrical potential across cell membranes, secretion and signal transduction. Close inspection of the physiological processes involved in channel function and the secondary structure of various ion channels has served as a basis for subdividing ion channels into a number of superfamilies. The voltage-gated ion channels are one of these superfamilies. Recent work has shown that mutations in various ion channel genes are responsible for a number of neuromuscular and neurological disorders. Correlation of the various mutations with the clinical phenotype is providing us with insight into the pathophysiology of these channel proteins. Interestingly, different mutations within the same gene may cause quite distinct clinical disorders, while mutations in different channel genes may result in very similar phenotypes (genetic heterogeneity). Examples of phenotypic variation and genetic heterogeneity are presented in the context of the periodic paralytic disorders of skeletal muscle, episodic ataxia, migraine, long QT syndrome and paroxysmal dyskinesia. Some of these disorders are known to be caused by mutations in ion channel genes, while in the episodic movement disorders, ion channel genes are considered excellent candidate genes.
Hum Mol Genet 1997
PMID:Phenotype variation and newcomers in ion channel disorders. 930 Jun 59

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.
Hum Mol Genet 1997 Oct
PMID:Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias. 930 75

The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.
Hum Mol Genet 1997 Nov
PMID:IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. 932 83

Mutations in the KvLQT1 gene are the cause for the long QT syndrome [Circulation 94:1996-2012 (1996)]. Coexpression of KvLQT1 in association with the channel regulator protein IsK produces a K+ current with characteristics reminiscent of the slow component of the delayed rectifier in cardiac myocytes. We explored the pharmacological properties of trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dime thyl- chromane (293B), a chromanol compound, on the K+ current produced by direct intranuclear injection of KvLQT1 and IsK cDNA plasmids in COS-7 cells. Injected cells were recorded by means of the whole-cell and cell-attached patch-clamp configurations under chloride-free conditions. Cells injected with KvLQT1 cDNA alone exhibited a fast-activating outward K+ current, whereas cells coinjected with KvLQT1 plus IsK cDNAs exhibited a time-dependent outward current with slower activation kinetics. The chromanol 293B blocked the K+ current related to KvLQT1 expression in both the absence or presence of IsK. The IC50 value for 293B to block KvLQT1-related current was not significantly modified by the presence of IsK (9.9 microM in the absence of IsK versus 9.8 microM in its presence). The block produced by 293B was strongly voltage-dependent inasmuch as it was close to 0 at -80 mV and occurred during a depolarizing voltage step. The time constants for the drug to block the current were in the same order of magnitude as activation kinetics of the current. Kinetics for drug unblock at the holding potential were much faster, in the order of a few tenths of a msec. KvLQT1 currents recorded in the cell-attached configuration were also blocked by externally applied 293B, suggesting that the compound penetrated the cell to block the channel. Cromakalim, another chromanol compound, also blocked KvLQT1 currents. Our results show that the chromanol compound 293B is targeted to KvLQT1 channels but not to the IsK regulator.
Mol Pharmacol 1997 Dec
PMID:KvLQT1 potassium channel but not IsK is the molecular target for trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl- chromane. 939 83

Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Two types of LQT have been reported, autosomal-dominant LQT (Romano-Ward syndrome) and autosomal-recessive LQT (Jervell and Lange-Nielsen syndrome); Jervell and Lange-Nielsen syndrome is also associated with deafness. Four LQT genes have been identified for autosomal-dominant LQT: K+ channel genes KVLQT1 on chromosome 11p15.5, HERG on 7q35-36 and minK on 21q22, and the cardiac Na+ channel gene SCN5A on chromosome 3p21-24. Two genes, KVLQT1 and minK, have been identified for Jervell and Lange-Nielsen syndrome. Genetic testing and gene-specific therapies are available for some LQT patients.
Mol Med Today 1998 Sep
PMID:The molecular basis of long QT syndrome and prospects for therapy. 979 61


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