Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome

We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of...

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Veröffentlicht in:Journal of molecular medicine (Berlin, Germany) Germany), 2004-03, Vol.82 (3), p.189-196
Hauptverfasser: SIYONG TENG, LIJUAN MA, RUTAI HUI, YINGXUE DONG, CHUNXIA LIN, JUE YE, BÄHRING, Robert, VARDANYAN, Vitya, YANZONG YANG, ZHIHU LIN, OLAF PONGS
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container_issue 3
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container_title Journal of molecular medicine (Berlin, Germany)
container_volume 82
creator SIYONG TENG
LIJUAN MA
RUTAI HUI
YINGXUE DONG
CHUNXIA LIN
JUE YE
BÄHRING, Robert
VARDANYAN, Vitya
YANZONG YANG
ZHIHU LIN
OLAF PONGS
description We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.
doi_str_mv 10.1007/s00109-003-0504-1
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Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. 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Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. 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Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>14714110</pmid><doi>10.1007/s00109-003-0504-1</doi><tpages>8</tpages></addata></record>
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subjects Animals
Base Sequence
Biological and medical sciences
Cardiac dysrhythmias
Cardiology. Vascular system
Cation Transport Proteins - chemistry
Cation Transport Proteins - genetics
Cell Membrane - metabolism
CHO Cells
Cloning, Molecular
Cricetinae
DNA Mutational Analysis
Electrophysiology - methods
Ether-A-Go-Go Potassium Channels
Female
Gene Deletion
General aspects
Haplotypes
Heart
Humans
Long QT Syndrome - genetics
Male
Medical sciences
Microscopy, Confocal
Models, Genetic
Molecular Sequence Data
Mutation
Patch-Clamp Techniques
Pedigree
Phenotype
Potassium Channels - chemistry
Potassium Channels - genetics
Potassium Channels, Voltage-Gated
Protein Structure, Tertiary
Structure-Activity Relationship
Time Factors
title Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome
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