HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects

Zhengfeng Zhou, Qiuming Gong, Miles L. Epstein, Craig T. January

Research output: Contribution to journalArticle

297 Citations (Scopus)

Abstract

Mutations in HERG are associated with human chromosome 7-linked congenital long QT (LQT-2) syndrome. We used electrophysiological, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum. Other mutations (1593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels. In contrast, the T474I mutation expressed HERG current but with altered gating properties. These findings suggest that the loss of HERG channel function in LQT-2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating.

Original languageEnglish (US)
Pages (from-to)21061-21066
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number33
DOIs
StatePublished - Aug 14 1998
Externally publishedYes

Fingerprint

Long QT Syndrome
Defects
Mutation
Chromosomes
Processing
Proteins
Chromosomes, Human, Pair 7
HEK293 Cells
Human Chromosomes
Endoplasmic Reticulum

ASJC Scopus subject areas

  • Biochemistry

Cite this

HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. / Zhou, Zhengfeng; Gong, Qiuming; Epstein, Miles L.; January, Craig T.

In: Journal of Biological Chemistry, Vol. 273, No. 33, 14.08.1998, p. 21061-21066.

Research output: Contribution to journalArticle

@article{9b0f60cdc50a4b5db258b1e50b14aa4c,
title = "HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects",
abstract = "Mutations in HERG are associated with human chromosome 7-linked congenital long QT (LQT-2) syndrome. We used electrophysiological, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum. Other mutations (1593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels. In contrast, the T474I mutation expressed HERG current but with altered gating properties. These findings suggest that the loss of HERG channel function in LQT-2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating.",
author = "Zhengfeng Zhou and Qiuming Gong and Epstein, {Miles L.} and January, {Craig T.}",
year = "1998",
month = "8",
day = "14",
doi = "10.1074/jbc.273.33.21061",
language = "English (US)",
volume = "273",
pages = "21061--21066",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "33",

}

TY - JOUR

T1 - HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects

AU - Zhou, Zhengfeng

AU - Gong, Qiuming

AU - Epstein, Miles L.

AU - January, Craig T.

PY - 1998/8/14

Y1 - 1998/8/14

N2 - Mutations in HERG are associated with human chromosome 7-linked congenital long QT (LQT-2) syndrome. We used electrophysiological, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum. Other mutations (1593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels. In contrast, the T474I mutation expressed HERG current but with altered gating properties. These findings suggest that the loss of HERG channel function in LQT-2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating.

AB - Mutations in HERG are associated with human chromosome 7-linked congenital long QT (LQT-2) syndrome. We used electrophysiological, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum. Other mutations (1593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels. In contrast, the T474I mutation expressed HERG current but with altered gating properties. These findings suggest that the loss of HERG channel function in LQT-2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating.

UR - http://www.scopus.com/inward/record.url?scp=0032516934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032516934&partnerID=8YFLogxK

U2 - 10.1074/jbc.273.33.21061

DO - 10.1074/jbc.273.33.21061

M3 - Article

C2 - 9694858

AN - SCOPUS:0032516934

VL - 273

SP - 21061

EP - 21066

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 33

ER -