The novel C-terminal KCNQ1 mutation M520R alters protein trafficking.

Nicole Schmitt; Kirstine Calloe; Nathalie Hélix Nielsen; Maria Buschmann; Erwin-Josef Speckmann; Eric Schulze-Bahr; Martin Schwarz

doi:10.1016/j.bbrc.2007.04.127

The novel C-terminal KCNQ1 mutation M520R alters protein trafficking.

Nicole Schmitt, Kirstine Calloe, Nathalie Hélix Nielsen, Maria Buschmann, Erwin-Josef Speckmann, Eric Schulze-Bahr, Martin Schwarz

24 Citations (Scopus)

Abstract

The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of the mutant did not reveal any whole-cell currents independent of the auxiliary subunit KCNE1. Co-expression of the wild-type Kv7.1 channels and the mutant showed that the mutant did not have a dominant negative effect. In immunocytochemical assays of transfected COS-1 cells wild-type Kv7.1 showed an immunopositive labeling of the plasma membrane. For M520R no plasma membrane staining was visible, instead a strong signal in the ER was observed. These results indicate that the LQT1 mutation M520R leads to ER-retention and dysfunctional trafficking of the mutant channel resulting in haploinsufficiency.
Udgivelsesdato: 2007-Jun-22

Original language	English
Journal	Biochemical and Biophysical Research Communications
Volume	358
Issue number	1
Pages (from-to)	304-10
Number of pages	6
ISSN	0006-291X
DOIs	https://doi.org/10.1016/j.bbrc.2007.04.127
Publication status	Published - 2007

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10.1016/j.bbrc.2007.04.127

Cite this

@article{9a98fe70e92211dcbee902004c4f4f50,

title = "The novel C-terminal KCNQ1 mutation M520R alters protein trafficking.",

abstract = "The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of the mutant did not reveal any whole-cell currents independent of the auxiliary subunit KCNE1. Co-expression of the wild-type Kv7.1 channels and the mutant showed that the mutant did not have a dominant negative effect. In immunocytochemical assays of transfected COS-1 cells wild-type Kv7.1 showed an immunopositive labeling of the plasma membrane. For M520R no plasma membrane staining was visible, instead a strong signal in the ER was observed. These results indicate that the LQT1 mutation M520R leads to ER-retention and dysfunctional trafficking of the mutant channel resulting in haploinsufficiency. Udgivelsesdato: 2007-Jun-22",

author = "Nicole Schmitt and Kirstine Calloe and Nielsen, {Nathalie H{\'e}lix} and Maria Buschmann and Erwin-Josef Speckmann and Eric Schulze-Bahr and Martin Schwarz",

note = "Keywords: Adult; Amino Acid Sequence; Animals; CHO Cells; COS Cells; Cell Membrane; Cercopithecus aethiops; Cricetinae; Cricetulus; Endoplasmic Reticulum; Female; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Middle Aged; Molecular Sequence Data; Mutation, Missense; Patch-Clamp Techniques; Pedigree; Protein Structure, Tertiary; Protein Transport",

year = "2007",

doi = "10.1016/j.bbrc.2007.04.127",

language = "English",

volume = "358",

pages = "304--10",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Elsevier",

number = "1",

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TY - JOUR

T1 - The novel C-terminal KCNQ1 mutation M520R alters protein trafficking.

AU - Schmitt, Nicole

AU - Calloe, Kirstine

AU - Nielsen, Nathalie Hélix

AU - Buschmann, Maria

AU - Speckmann, Erwin-Josef

AU - Schulze-Bahr, Eric

AU - Schwarz, Martin

N1 - Keywords: Adult; Amino Acid Sequence; Animals; CHO Cells; COS Cells; Cell Membrane; Cercopithecus aethiops; Cricetinae; Cricetulus; Endoplasmic Reticulum; Female; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Middle Aged; Molecular Sequence Data; Mutation, Missense; Patch-Clamp Techniques; Pedigree; Protein Structure, Tertiary; Protein Transport

PY - 2007

Y1 - 2007

N2 - The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of the mutant did not reveal any whole-cell currents independent of the auxiliary subunit KCNE1. Co-expression of the wild-type Kv7.1 channels and the mutant showed that the mutant did not have a dominant negative effect. In immunocytochemical assays of transfected COS-1 cells wild-type Kv7.1 showed an immunopositive labeling of the plasma membrane. For M520R no plasma membrane staining was visible, instead a strong signal in the ER was observed. These results indicate that the LQT1 mutation M520R leads to ER-retention and dysfunctional trafficking of the mutant channel resulting in haploinsufficiency. Udgivelsesdato: 2007-Jun-22

AB - The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of the mutant did not reveal any whole-cell currents independent of the auxiliary subunit KCNE1. Co-expression of the wild-type Kv7.1 channels and the mutant showed that the mutant did not have a dominant negative effect. In immunocytochemical assays of transfected COS-1 cells wild-type Kv7.1 showed an immunopositive labeling of the plasma membrane. For M520R no plasma membrane staining was visible, instead a strong signal in the ER was observed. These results indicate that the LQT1 mutation M520R leads to ER-retention and dysfunctional trafficking of the mutant channel resulting in haploinsufficiency. Udgivelsesdato: 2007-Jun-22

U2 - 10.1016/j.bbrc.2007.04.127

DO - 10.1016/j.bbrc.2007.04.127

M3 - Journal article

C2 - 17482572

SN - 0006-291X

VL - 358

SP - 304

EP - 310

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 1

ER -