Schmitt Nicole, Calloe Kirstine, Nielsen Nathalie Hélix, Buschmann Maria, Speckmann Erwin-Josef, Schulze-Bahr Eric, Schwarz Martin
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.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):304-10. doi: 10.1016/j.bbrc.2007.04.127. Epub 2007 Apr 27.
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.
长QT综合征的特征是QT间期延长以及导致晕厥和猝死的快速性心律失常。我们在一个患有长QT综合征的德国家庭的Kv7.1通道钙调蛋白结合域中鉴定出错义突变M520R。该突变体的异源表达未显示出任何独立于辅助亚基KCNE1的全细胞电流。野生型Kv7.1通道与该突变体的共表达表明该突变体没有显性负效应。在转染的COS-1细胞的免疫细胞化学分析中，野生型Kv7.1显示出质膜的免疫阳性标记。对于M520R，未观察到质膜染色，相反，在内质网中观察到强信号。这些结果表明，LQT1突变M520R导致突变通道在内质网滞留和功能失调的运输，从而导致单倍剂量不足。
