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

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 -