Novel mechanism associated with an inherited cardiac arrhythmia

Defective protein trafficking by the mutant HERG (G601S) potassium channel

Michiko Furutani, Matthew C. Trudeau, Nobuhisa Hagiwara, Akiko Seki, Qiuming Gong, Zhengfeng Zhou, Shin Ichiro Imamura, Hirotaka Nagashima, Hiroshi Kasanuki, Atsuyoshi Takao, Kazuo Momma, Craig T. January, Gail A. Robertson, Rumiko Matsuoka

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Background - The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go- related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (I(Kr)), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. Methods and Results - To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. Conclusions - Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.

Original languageEnglish (US)
Pages (from-to)2290-2294
Number of pages5
JournalCirculation
Volume99
Issue number17
StatePublished - May 4 1999
Externally publishedYes

Fingerprint

Potassium Channels
Protein Transport
Long QT Syndrome
Ether
Cardiac Arrhythmias
Xenopus
Genes
Oocytes
Human Trafficking
Western Blotting
Mutation
Chromosomes, Human, Pair 7
HEK293 Cells
Missense Mutation
Green Fluorescent Proteins
Action Potentials
Cell Membrane

Keywords

  • Arrhythmia
  • Genes
  • Long-QT syndrome

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Novel mechanism associated with an inherited cardiac arrhythmia : Defective protein trafficking by the mutant HERG (G601S) potassium channel. / Furutani, Michiko; Trudeau, Matthew C.; Hagiwara, Nobuhisa; Seki, Akiko; Gong, Qiuming; Zhou, Zhengfeng; Imamura, Shin Ichiro; Nagashima, Hirotaka; Kasanuki, Hiroshi; Takao, Atsuyoshi; Momma, Kazuo; January, Craig T.; Robertson, Gail A.; Matsuoka, Rumiko.

In: Circulation, Vol. 99, No. 17, 04.05.1999, p. 2290-2294.

Research output: Contribution to journalArticle

Furutani, M, Trudeau, MC, Hagiwara, N, Seki, A, Gong, Q, Zhou, Z, Imamura, SI, Nagashima, H, Kasanuki, H, Takao, A, Momma, K, January, CT, Robertson, GA & Matsuoka, R 1999, 'Novel mechanism associated with an inherited cardiac arrhythmia: Defective protein trafficking by the mutant HERG (G601S) potassium channel', Circulation, vol. 99, no. 17, pp. 2290-2294.
Furutani, Michiko ; Trudeau, Matthew C. ; Hagiwara, Nobuhisa ; Seki, Akiko ; Gong, Qiuming ; Zhou, Zhengfeng ; Imamura, Shin Ichiro ; Nagashima, Hirotaka ; Kasanuki, Hiroshi ; Takao, Atsuyoshi ; Momma, Kazuo ; January, Craig T. ; Robertson, Gail A. ; Matsuoka, Rumiko. / Novel mechanism associated with an inherited cardiac arrhythmia : Defective protein trafficking by the mutant HERG (G601S) potassium channel. In: Circulation. 1999 ; Vol. 99, No. 17. pp. 2290-2294.
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AU - Trudeau, Matthew C.

AU - Hagiwara, Nobuhisa

AU - Seki, Akiko

AU - Gong, Qiuming

AU - Zhou, Zhengfeng

AU - Imamura, Shin Ichiro

AU - Nagashima, Hirotaka

AU - Kasanuki, Hiroshi

AU - Takao, Atsuyoshi

AU - Momma, Kazuo

AU - January, Craig T.

AU - Robertson, Gail A.

AU - Matsuoka, Rumiko

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N2 - Background - The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go- related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (I(Kr)), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. Methods and Results - To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. Conclusions - Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.

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