Additional Gene Variants Reduce Effectiveness of Beta‐Blockers in the LQT1 Form of Long QT Syndrome

Kobori, Atsushi; Sarai, Nobuaki; Shimizu, Wataru; Nakamura, Yoshihide; Murakami, Yosuke; Makiyama, Takeru; Ohno, Seiko; Takenaka, Kotoe; Ninomiya, T.; Fujiwara, Yuichiro; Matsuoka, Satoshi; Takano, Makoto; Noma, Akinori; Kita, Toru; Horie, Minoru

doi:10.1046/j.1540-8167.2004.03212.x

Cited by 31 publications

(24 citation statements)

References 46 publications

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“…This system avoids the potential confounding influence of endogenous KCNQ1 and KCNE channel subunits that exist in Xenopus oocytes and the uncertainties associated with transient transfection of multiple separate plasmids in COS7 cells. 20 Our findings indicate that KCNQ1-A341V exerts a dominant-negative effect on I Ks and therefore is not a pure loss-of-function mutation. This is more consistent with an allele associated with a severe clinical phenotype.…”

Section: Dominant Suppression Of I Ks By Kcnq1-a341vmentioning

confidence: 64%

“…Consistent with the autosomal dominant inheritance of Romano-Ward syndrome, many KCNQ1 mutations exert dominant negative effects on the wild-type channel in heterologous expression systems, whereas mutations associated with the Jervell and LangeNielsen syndrome are typically pure loss-of-function alleles. Previous characterization of KCNQ1-A341V in oocytes [17][18][19] or COS7 cells 20 demonstrated little or no dominant activity of this mutation, suggesting that it may be associated with a milder form of the disease. However, our survey of the phenotype associated with this allele indicates that it confers a more severe clinical picture (Figures 5 and 6).…”

Section: Dominant Suppression Of I Ks By Kcnq1-a341vmentioning

confidence: 93%

“…20 These studies reported that this allele is a simple loss-of-function mutation that does not exhibit a dominant negative effect on wild-type KCNQ1, suggesting that it may cause less severe disease. However, oocytes express an endogenous Xenopus KCNQ1 21 and multiple KCNE accessory subunits.…”

Section: Functional Characterization Of Kcnq1-a341vmentioning

confidence: 99%

“…In these experiments, we recognized the need to verify coexpression of wild-type and mutant KCNQ1 along with the KCNE1 accessory subunit, a potential confounding variable for interpreting previously reported COS7 cell data. 20 Therefore, we transiently transfected KCNQ1-A341V-IRES-EGFP into CHO cells stably expressing consistent levels of wild-type KCNQ1 with KCNE1 (stable I Ks cell line). We then performed whole-cell patch-clamp recording on cells exhibiting green fluorescence, ie, cells coexpressing both A341V and both subunits for I Ks (Figure 7).…”

Section: Functional Characterization Of Kcnq1-a341vmentioning

confidence: 99%

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Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

et al. 2005

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Background-In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results-The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers.When not taking ␤-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (Յ440 ms). A QTc Ͼ500 ms was associated with increased risk for cardiac events (ORϭ4.22; 95% CI, 1.12 to 15.80; Pϭ0.033). We also found that MCs with a heart rate Ͻ73 bpm were at significantly lower risk (ORϭ0.23; 95% CI, 0.06 to 0.86; Pϭ0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7Ϯ4 versus 13Ϯ9 years, both PϽ0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions-KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. (Circulation. 2005;112:2602-2610.)

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Section: Dominant Suppression Of I Ks By Kcnq1-a341vmentioning

confidence: 64%

Section: Dominant Suppression Of I Ks By Kcnq1-a341vmentioning

confidence: 93%

Section: Functional Characterization Of Kcnq1-a341vmentioning

confidence: 99%

Section: Functional Characterization Of Kcnq1-a341vmentioning

confidence: 99%

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Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

et al. 2005

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“…21,22 Later, Brink et al 5 demonstrated that this mutation was associated with a mild dominant-negative effect with a loss in Figure 6. Unadjusted Kaplan-Meier estimate of the cumulative event-free survival (any first event) among patients with a mild (A341V) and strong (G314S) dominant-negative mutation.…”

Section: Mutation Site Functional Effects and Clinical Severitymentioning

confidence: 99%

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

et al. 2007

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Background-The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results-Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484Ϯ42 versus 485Ϯ45 ms (PϭNS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485Ϯ43 versus 465Ϯ38 ms) (all PϽ0.001). Arrhythmic risk remained higher (PϽ0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite ␤-blocker therapy. Conclusions-The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.

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The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

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Additional Gene Variants Reduce Effectiveness of Beta‐Blockers in the LQT1 Form of Long QT Syndrome

Abstract: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.

Cited by 31 publications

References 46 publications

Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

The genetic basis of long QT and short QT syndromes: A mutation update

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