Four Novel
            <i>KVLQT1</i>
            and Four Novel
            <i>HERG</i>
            Mutations in Familial Long-QT Syndrome

Tanaka, Toshihiro; Nagai, Ryozo; Tomoike, Hitonobu; Takata, Shigeo; Yano, Katsusuke; Yabuta, Keijiro; Haneda, Noriyuki; Nakano, Osami; Shibata, Akira; Sawayama, Toshitami; Kasai, Hideaki; Yazaki, Yoshio; Nakamura, Yusuke

doi:10.1161/01.cir.95.3.565

Cited by 109 publications

(76 citation statements)

References 15 publications

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“…Inherited loss-of-function mutations of Kv7.1 and KCNE1 are associated with long QT syndrome (LQT), in which the ventricular action potential duration is prolonged, resulting in a high risk of ventricular arrhythmias and sudden death. Eleven previously reported LQT-associated mutations (39)(40)(41)(42)(43)(44)(45)(46) affect basic residues in the PIP 2 pocket (Table S1). For these mutations, loss of VSD-PD coupling may compromise the I Ks channel function and create a substrate for cardiac arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Zaydman

Silva

Delaloye

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

180

313

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Voltage-gated ion channels generate dynamic ionic currents that are vital to the physiological functions of many tissues. These proteins contain separate voltage-sensing domains, which detect changes in transmembrane voltage, and pore domains, which conduct ions. Coupling of voltage sensing and pore opening is critical to the channel function and has been modeled as a protein-protein interaction between the two domains. Here, we show that coupling in Kv7.1 channels requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We found that voltage-sensing domain activation failed to open the pore in the absence of PIP 2 . This result is due to loss of coupling because PIP 2 was also required for pore opening to affect voltage-sensing domain activation. We identified a critical site for PIP 2 -dependent coupling at the interface between the voltage-sensing domain and the pore domain. This site is actually a conserved lipid-binding site among different K + channels, suggesting that lipids play an important role in coupling in many ion channels.V oltage-gated ion channels are integral membrane proteins that sense membrane voltage and respond by opening or closing a transmembrane pore. Ionic currents carried by voltage-gated ion channels control contraction in muscle, encode information in the nervous system, and trigger secretion in neurohormonal tissues. Voltage-gated ion channels contain four voltage-sensing domains (VSDs) and a central pore domain (PD) that are structurally distinct (1, 2). In voltage-gated potassium (Kv) channels, the first four transmembrane segments (S1-S4) of each α-subunit forms a VSD. In response to changes in transmembrane voltage, the VSD undergoes a conformational change, called activation, during which membrane depolarization moves the S4 segment outward (3). The PD is formed by the last two transmembrane segments (S5, S6) from four α-subunits and undergoes a mainly voltageindependent conformational change during which the intracellular ends of the S6 segments bend, opening the ionic pore (4, 5). Interestingly, the PD and VSD can exist in pore-only (6) and voltage sensor-only proteins, respectively, where they function independently (7,8). Confining sensitivity to voltage, or to other stimuli, within a domain diversifies the ion channel properties that can be achieved by partnering different pore and sensor domains. However, this modular architecture also raises a fundamental question as to how VSD activation is transmitted to the PD. Previous studies of this coupling process have revealed the importance of direct protein-protein interactions at the VSD-PD interface (9-13); however, the possible role of membrane lipids in VSD-PD coupling remains undetermined.The membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) modulates the activity of many ion channels, including some voltage-gated channels (14). Notably, all members of the Kv7 family (Kv7.1-Kv7.5), which play important physiological roles in the cardiac (15) or the nervous (16) systems, require PIP 2 to be opened by...

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Section: Discussionmentioning

confidence: 99%

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Zaydman

Silva

Delaloye

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

180

313

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“…Moreover, the 30 RW patients of this table do not include 7 individuals who died suddenly without knowledge of their ECG 11 . Additional RW mutations have been reported in the pore of KvLQT1 without knowledge of the corresponding QTc values: G306R, T312I and I313M 7,14 .…”

Section: Discussionmentioning

confidence: 99%

Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome

et al. 1998

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Mutations in KvLQT1, a gene encoding a potassium channel, cause both the recessive Jervell and Lange-Nielsen (JLN) syndrome and the dominant Romano-Ward (RW) syndrome. These diseases are characterised by a prolonged QT interval on the ECG, syncopes and sudden death due to cardiac arrhythmias. The JLN syndrome is also associated with a congenital bilateral deafness. We report here a novel missense mutation, W305S, in the pore region of KvLQT1 identified by PCR-SSCP analysis in two consanguineous JLN families. In contrast to several missense mutations found in the same region of KvLQT1 in RW patients which are associated with severe cardiac phenotypes, the W305S mutation is responsible for an apparently normal phenotype in heterozygous JLN carriers.

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“…In control conditions, N629D strongly colocalized with Bap31 but this colocalization decreased after treatment in E-4031 for 12 h (PC ϭ 0.69 Ϯ 0.01, n ϭ 8 images, PC ϭ 0.53 Ϯ 0.01, n ϭ 8 images, respectively, P Ͻ 0.05). We also performed a negative-control experiment with cells expressing trafficking-deficient LQT2 mutation A614V (37). Similar to G601S, A614V is linked to LQT2 in several unrelated families (Table 1); however, unlike G601S, A614V does not undergo pharmacological correction with E-4031 (3).…”

Section: E-4031 Increases the Trafficking Of G601s From The Transitiomentioning

confidence: 99%