Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family

Ma, Lijuan; Lin, Chunqing; Teng, Siyong; Chai, Yifeng; Bähring, Robert; Vardanyan, Vitya; Li, Liang; Pongs, Olaf; Hui, Rutai

doi:10.1016/s0008-6363(03)00510-8

Cited by 30 publications

(34 citation statements)

References 31 publications

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“…Specifically, we made a detailed study of T58P/L59P which occurs in JLNS (10,31). We also examined G52R (RWS), S74L (RWS), and R98W (RWS) for comparison (16,22,28). We chose to compare the effects of T58P/L59P with G52R, S74L, and R98W because, like T58P/L59P, their effects on trafficking or assembly of the I Ks complex have not been determined.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of disease pathogenesis in long QT syndrome type 5

Harmer

Wilson

Aldridge

et al. 2010

American Journal of Physiology-Cell Physiology

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KCNE1 associates with the pore-forming alpha-subunit KCNQ1 to generate the slow (I(Ks)) current in cardiac myocytes. Mutations in either KCNQ1 or KCNE1 can alter the biophysical properties of I(Ks) and mutations in KCNE1 underlie cases of long QT syndrome type 5 (LQT5). We previously investigated a mutation in KCNE1, T58P/L59P, which causes severe attenuation of I(Ks). However, how T58P/L59P acts to disrupt I(Ks) has not been determined. In this study, we investigate and compare the effects of T58P/L59P with three other LQT5 mutations (G52R, S74L, and R98W) on the biophysical properties of the current, trafficking of KCNQ1, and assembly of the I(Ks) channel. G52R and T58P/L59P produce currents that lack the kinetic behavior of I(Ks). In contrast, S74L and R98W both produce I(Ks)-like currents but with rightward shifted voltage dependence of activation. All of the LQT5 mutants express protein robustly, and T58P/L59P and R98W cause modest, but significant, defects in the trafficking of KCNQ1. Despite defects in trafficking, in the presence of KCNQ1, T58P/L59P and the other LQT5 mutants are present at the plasma membrane. Interestingly, in comparison to KCNE1 and the other LQT5 mutants, T58P/L59P associates only weakly with KCNQ1. In conclusion, we identify the disease mechanisms for each mutation and reveal that T58P/L59P causes disease through a novel mechanism that involves defective I(Ks) complex assembly.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of disease pathogenesis in long QT syndrome type 5

Harmer

Wilson

Aldridge

et al. 2010

American Journal of Physiology-Cell Physiology

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“…F54V is a missense mutation in the transmembrane domain. F54V is near KCNE1 G52R, which has a abnormal biophysical phenotype underlie the molecular mechanism of ventricular arrhythmias and sudden death in G52R carriers [19]. Tapper has proved that without the participation of the transmembrane domain of KCNE1, the C-terminus of KCNE1 cannot regulate the function of KCNQ1 channels alone [20].…”

Section: Discussionmentioning

confidence: 99%

Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population

Liu¹,

Zhao

et al. 2013

Forensic Science International

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“…Legend:To validate the pharmacological implication of KCNQ1 using gene-specific molecular reagents, embryos at the 1-cell stage were injected with synthetic mRNA encoding dominant-negative XKCNQ1 proteins. While embryos injected with β-gal mRNA (negative control) only exhibited the normal background of heterotaxia, misexpression of the mutant V244M [71], L104P [62], and the double mutant L104P+V244M all caused significant levels of heterotaxia (p<<0.01), as did the dominant negative mutant of XKCNE1, G46R [64]. Table 2B.…”

Section: Cloning Of Native Frog Kcnq1 and Kcne1mentioning

confidence: 99%

“…A homologous dominantnegative (DN) mutation (hKCNE1_G52R, [64]) was introduced using primers xE1_G46R down [5'-GAT TCT TCG GCT TTT TTA CTT TTG GGA TAA-3'] and xE1_G46R mut-up [5'-GCA GCA GTA GAA GGA TAT ACA CCA CTT CCA-3'], constructing pxE1_G46R(DN). Nucleotide sequences were confirmed by DNA sequencing.…”

Section: Cloning and Plasmid Construction Of Xenopus Laevis Kcnq1 Andmentioning

confidence: 99%

“…dominant negative mutant of XKCNE1, G46R (a mutation in the transmembrane domain that reduces the channel complex's current to about half of its normal value [64]), also caused significant levels of heterotaxia (p<<0.01, Table 2A). Thus, it is likely that XKCNE1 is required for LR patterning, and that the dominant negative construct acts by impairing endogenous XKCNQ1-XKCNE1 complex function.…”

Section: Figmentioning

confidence: 99%

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KCNQ1 and KCNE1 K<sup>+</sup> Channel Components are Involved in Early Left-Right Patterning in <i>Xenopus laevis</i> Embryos

Morokuma¹,

Blackiston²,

Levin³

2008

Cell Physiol Biochem

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Several ion transporters have been implicated in left-right (LR) patterning. Here, we characterize a new component of the early bioelectrical circuit: the potassium channel KCNQ1 and its accessory subunit KCNE1. Having cloned the native Xenopus versions of both genes, we show that both are asymmetrically localized as maternal proteins during the first few cleavages of frog embryo development in a process dependent on microtubule and actin organization. Molecular loss-of-function using dominant negative constructs demonstrates that both gene products are required for normal LR asymmetry. We propose a model whereby these channels provide an exit path for K⁺ ions brought in by the H⁺,K⁺-ATPase. This physiological module thus allows the obligate but electroneutral H⁺,K⁺-ATPase to generate an asymmetric voltage gradient on the left and right sides. Our data reveal a new, bioelectrical component of the mechanisms patterning a large-scale axis in vertebrate embryogenesis.

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Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family

Cited by 30 publications

References 31 publications

Mechanisms of disease pathogenesis in long QT syndrome type 5

Mechanisms of disease pathogenesis in long QT syndrome type 5

Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population

KCNQ1 and KCNE1 K<sup>+</sup> Channel Components are Involved in Early Left-Right Patterning in <i>Xenopus laevis</i> Embryos

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Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family

Cited by 30 publications

References 31 publications

Mechanisms of disease pathogenesis in long QT syndrome type 5

Mechanisms of disease pathogenesis in long QT syndrome type 5

Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population

KCNQ1 and KCNE1 K<sup>&plus;</sup> Channel Components are Involved in Early Left-Right Patterning in <i>Xenopus laevis</i> Embryos

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KCNQ1 and KCNE1 K<sup>+</sup> Channel Components are Involved in Early Left-Right Patterning in <i>Xenopus laevis</i> Embryos