The novel C-terminal KCNQ1 mutation M520R alters protein trafficking |
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Authors: | Schmitt Nicole Calloe Kirstine Nielsen Nathalie Hélix Buschmann Maria Speckmann Erwin-Josef Schulze-Bahr Eric Schwarz Martin |
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Institution: | Department of Biomedical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. nschmitt@mfi.ku.dk |
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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. |
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Keywords: | Arrhythmia Long QT syndrome KCNQ1 Kv7 1 Trafficking |
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