Functional Effects of Mutations in KvLQT1 that Cause Long QT Syndrome

Wang, Z; Tristani‐Firouzi, Martin; Xu, Qingyang; Lin, Monica; Keating, Mark T.; Sanguinetti, Michael C.

doi:10.1111/j.1540-8167.1999.tb00262.x

Cited by 87 publications

(68 citation statements)

References 31 publications

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“…These changes were most pronounced for the W248R mutation, resulting in a current that grossly resembled I Ks (3,4,25). We previously reported the functional consequences of another LQT-associated mutation, V254M, located in the S4-S5 linker of KvLQT1 (8). This mutant caused loss of function, but coassembly of mutant subunits with WT KvLQT1 accelerated the rate of channel activation.…”

Section: Mutations In the S4-s5 Linker Alter Gating Properties Ofmentioning

confidence: 89%

“…LQT-associated Mutations in KvLQT1 Decrease I Ks -Mutations in KVLQT1 that cause one type of autosomal dominant LQT usually result in loss of channel function and a dominantnegative effect (7)(8)(9)(10). In this study, we characterized the functional consequences of three LQT-associated missense mutations located in or adjacent to the S4-S5 linker of KvLQT1.…”

Section: Mutations In the S4-s5 Linker Alter Gating Properties Ofmentioning

confidence: 99%

“…Mutations in KVLQT1 (also called KCNQ1) cause long QT syndrome (LQT) (5), an inherited disorder of ventricular repolarization that predisposes affected individuals to cardiac arrhythmias and sudden death (6). The physiologic consequences of some mutations have been studied by heterologous expression of KvLQT1 in Xenopus oocytes or mammalian cells (7)(8)(9)(10). Most missense mutations in KVLQT1 cause loss of channel function when mutant subunits are expressed alone and a dominantnegative effect when coexpressed with wild-type (WT) KvLQT1 subunits.…”

mentioning

confidence: 99%

“…However, some mutations alter the function of Kv-LQT1 channels, and a study of their biophysical properties has led to novel insights into the structural basis of channel function. For example, the LQT-associated mutation V254M caused loss of function but accelerated activation of KvLQT1 channel current when mutant subunits were coexpressed with WT Kv-LQT1 subunits (8). V254M is located in the cytosolic loop connecting the S4 and S5 transmembrane domains of KvLQT1.…”

mentioning

confidence: 99%

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Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits

Franqueza¹,

Lin²,

Splawski³

et al. 1999

Journal of Biological Chemistry

104

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Long QT syndrome is an inherited disorder of cardiac repolarization caused by mutations in cardiac ion channel genes, including KVLQT1. In this study, the functional consequences of three long QT-associated missense mutations in KvLQT1 (R243C, W248R, E261K) were characterized using the Xenopus oocyte heterologous expression system and two-microelectrode voltage clamp techniques. These mutations are located in or near the intracellular linker between the S4 and S5 transmembrane domains, a region implicated in activation gating of potassium channels. The E261K mutation caused loss of function and did not interact with wildtype KvLQT1 subunits. R243C or W248R KvLQT1 subunits formed functional channels, but compared with wild-type KvLQT1 current, the rate of activation was slower, and the voltage dependence of activation and inactivation was shifted to more positive potentials. Co expression of minK and KvLQT1 channel subunits induces a slow delayed rectifier K ؉ current, I Ks , characterized by slow activation and a markedly increased magnitude compared with current induced by KvLQT1 subunits alone. Coexpression of minK with R243C or W248R KvLQT1 subunits suppressed current, suggesting that coassembly of mutant subunits with minK prevented normal channel gating. The decrease in I Ks caused by loss of function or altered gating properties explains the prolonged QT interval and increased risk of arrhythmia and sudden death associated with these mutations in KVLQT1.The slow delayed rectifier K ϩ current, I Ks , 1 is one of several outward currents that modulate repolarization of cardiac action potentials (1, 2). The channel mediating I Ks is formed by coassembly of two subunits, minK and KvLQT1 (3, 4). Mutations in KVLQT1 (also called KCNQ1) cause long QT syndrome (LQT) (5), an inherited disorder of ventricular repolarization that predisposes affected individuals to cardiac arrhythmias and sudden death (6). The physiologic consequences of some mutations have been studied by heterologous expression of KvLQT1 in Xenopus oocytes or mammalian cells (7-10). Most missense mutations in KVLQT1 cause loss of channel function when mutant subunits are expressed alone and a dominantnegative effect when coexpressed with wild-type (WT) KvLQT1 subunits. However, some mutations alter the function of Kv-LQT1 channels, and a study of their biophysical properties has led to novel insights into the structural basis of channel function. For example, the LQT-associated mutation V254M caused loss of function but accelerated activation of KvLQT1 channel current when mutant subunits were coexpressed with WT Kv-LQT1 subunits (8). V254M is located in the cytosolic loop connecting the S4 and S5 transmembrane domains of KvLQT1. Missense mutations in the S4-S5 linker have also been reported to accelerate activation and deactivation of human ether-a-go-go-related gene (HERG) channels (11). Furthermore, the S4-S5 linker determines the rate of deactivation of chimeric channels constructed from Kv2.1 and Kv3.1 (12). Together, these studies indicate th...

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Section: Mutations In the S4-s5 Linker Alter Gating Properties Ofmentioning

confidence: 89%

Section: Mutations In the S4-s5 Linker Alter Gating Properties Ofmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits

Franqueza¹,

Lin²,

Splawski³

et al. 1999

Journal of Biological Chemistry

104

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“…The potassium channel thought to be involved in long QT syndrome in human heart pathology (Wang et al, 1999), K(v)LQT-1, is also expressed in the primitive streak in the chick (Fig. 4G) and then in most tissues at early somite stages (Fig.…”

Section: K(v)lqt-1 (Kcnq1)mentioning

confidence: 99%

Early embryonic expression of ion channels and pumps in chick and Xenopus development

Rutenberg

Cheng²,

Levin³

2002

Developmental Dynamics

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An extensive body of literature implicates endogenous ion currents and standing voltage potential differences in the control of events during embryonic morphogenesis. Although the expression of ion channel and pump genes, which are responsible for ion flux, has been investigated in detail in nervous tissues, little data are available on the distribution and function of specific channels and pumps in early embryogenesis. To provide a necessary basis for the molecular understanding of the role of ion flux in development, we surveyed the expression of ion channel and pump mRNAs, as well as other genes that help to regulate membrane potential. Analysis in two species, chick and Xenopus, shows that several ion channel and pump mRNAs are present in specific and dynamic expression patterns in early embryos, well before the appearance of neurons. Examination of the distribution of maternal mRNAs reveals complex spatiotemporal subcellular localization patterns of transcripts in early blastomeres in Xenopus. Taken together, these data are consistent with an important role for ion flux in early embryonic morphogenesis; this survey characterizes candidate genes and provides information on likely embryonic contexts for their function, setting the stage for functional studies of the morphogenetic roles of ion transport.

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Detection of a new KCNQ1 frameshift mutation associated with Jervell and Lange‐Nielsen syndrome in 2 Iranian families

Amirian

Zafari

Dalili

et al. 2018

Journal of Arrhythmia

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Jervell‐Lange Nielsen syndrome (JLNS) with autosomal recessive inheritance is a congenital cardiovascular disorder characterized by prolongation of QT interval on the ECG and deafness. We have performed molecular investigation by haplotype analysis and DNA Sanger sequencing in 2 unrelated Iranian families with a history of syncope. Mutational screening of KCNQ1 gene revealed the novel homozygous frameshift mutation c.733‐734delGG (p.G245Rfs*39) in 2 obviously unrelated cases of JLNS which is probably a founder mutation in Iran. The novel mutation detected in this study is the first time reported among Iranian population and will be beneficial in the tribe and region‐specific cascade screening of LQTS in Iran.

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Functional Effects of Mutations in KvLQT1 that Cause Long QT Syndrome

Cited by 87 publications

References 31 publications

Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits

Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits

Early embryonic expression of ion channels and pumps in chick and Xenopus development

Detection of a new KCNQ1 frameshift mutation associated with Jervell and Lange‐Nielsen syndrome in 2 Iranian families

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