Abstract:The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including b-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. … Show more
“…The concept of modifier genes, including compound heterozygosity 26 and the addition of single-nucleotide polymorphisms (SNPs) 27,28 to LQTS mutations, has been proposed to explain the phenomenon of phenotypic heterogeneity. 29 Although modifier genes have previously been reported in the context of amplifying the effect of LQTS mutations, 26 -28 a recent study has provided some evidence that SNPs might ameliorate the clinical phenotype of a LQTS mutation. 30 A possible explanation to the discrepancy between in vitro and clinical phenotype found in the Swedish Y111C population could be the existence of a modifying SNP that very closely accompanies the deleterious mutation in these individuals.…”
Section: Potential Role Of Modifying Factorsmentioning
Background-A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events. Methods and Results-We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers Ͻ40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25Ϯ20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, Pϭ0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (nϭ24) and family members (nϭ83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915. Conclusions-The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome. (Circ Cardiovasc Genet. 2009;2:558-564.)
“…The concept of modifier genes, including compound heterozygosity 26 and the addition of single-nucleotide polymorphisms (SNPs) 27,28 to LQTS mutations, has been proposed to explain the phenomenon of phenotypic heterogeneity. 29 Although modifier genes have previously been reported in the context of amplifying the effect of LQTS mutations, 26 -28 a recent study has provided some evidence that SNPs might ameliorate the clinical phenotype of a LQTS mutation. 30 A possible explanation to the discrepancy between in vitro and clinical phenotype found in the Swedish Y111C population could be the existence of a modifying SNP that very closely accompanies the deleterious mutation in these individuals.…”
Section: Potential Role Of Modifying Factorsmentioning
Background-A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events. Methods and Results-We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers Ͻ40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25Ϯ20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, Pϭ0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (nϭ24) and family members (nϭ83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915. Conclusions-The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome. (Circ Cardiovasc Genet. 2009;2:558-564.)
“…Current treatments for inherited LQTS include the administration of -adrenergic receptor blockers, left cardiac sympathetic denervation, or implantation of cardiac defibrillators for the most severe cases (8). However, pharmacologic treatment is not always effective (9) and surgery or devices are expensive and require invasive procedures.…”
Activation of human ether-a-go-go-related gene 1 (hERG1) K ؉ channels mediates cardiac action potential repolarization. Drugs that activate hERG1 channels represent a mechanism-based approach for the treatment of long QT syndrome, a disorder of cardiac repolarization associated with ventricular arrhythmia and sudden death. Here, we characterize the mechanisms of action and the molecular determinants for binding of RPR260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR), a recently discovered hERG1 channel activator. Channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured by using the two-microelectrode voltage-clamp technique. RPR induced a concentration-dependent slowing in the rate of channel deactivation and enhanced current magnitude by shifting the voltage dependence of inactivation to more positive potentials. This mechanism was confirmed by demonstrating that RPR slowed the rate of deactivation, but did not increase current magnitude of inactivation-deficient mutant channels. The effects of RPR on hERG1 kinetics and magnitude could be simulated by reducing three rate constants in a Markov model of channel gating. Point mutations of specific residues located in the S4 -S5 linker or cytoplasmic ends of the S5 and S6 domains greatly attenuated or ablated the effects of 3 M RPR on deactivation (five residues), inactivation (one residue), or both gating mechanisms (four residues). These findings define a putative binding site for RPR and confirm the importance of an interaction between the S4 -S5 linker and the S6 domain in electromechanical coupling of voltage-gated K ؉ channels.voltage clamp ͉ Xenopus ͉ long QT syndrome H uman ether-a-go-go-related gene 1 (hERG1) ␣-subunits coassemble to form channels that conduct I Kr (1-3), the rapid delayed rectifier K ϩ current that contributes to normal repolarization of cardiac action potentials (4). Loss-of-function mutations in hERG1 cause inherited long QT syndrome (LQTS), a disorder characterized by delayed repolarization of ventricular action potentials and prolonged QT interval of the body surface electrocardiogram (5). The acquired form of LQTS is more common and is most often caused by unintended block of hERG1 channels by a plethora of common medications (6). Inherited and acquired LQTS are associated with an increased risk of torsades de pointes, an arrhythmia that can degenerate into ventricular fibrillation and cause sudden death (7).Current treatments for inherited LQTS include the administration of -adrenergic receptor blockers, left cardiac sympathetic denervation, or implantation of cardiac defibrillators for the most severe cases (8). However, pharmacologic treatment is not always effective (9) and surgery or devices are expensive and require invasive procedures. Acute episodes of drug-induced LQTS are treated with magnesium sulfate administration and discontinued use of the suspect medication. Activation of hERG1 could provide an...
“…A higher efficacy in treating LQT3 is obtained by combining beta--blockers with mexiletine. However, such treatment is not equally effective in all patients [4]. The manifestations described above are typical clinical manifestations of LQT3.…”
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