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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

Biochem. Biophys. Res. Commun., 2007 Jun 22 , 358, 304-10

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.