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Congenital long QT syndrome caused by the F275S KCNQ1 mutation: mechanism of impaired channel function.

Wei Li, Qiu-fen Wang, Rong Du, Qiu-Mei Xu, Qin-Mei Ke, Bin Wang, Xue-Lin Chen, Li Tian, Shou-Yan Zhang, Cai-Lian Kang, Si-Ming Guan, Jun-Guo Yang, Zi-Fang Song

Biochem. Biophys. Res. Commun., 2009 Feb 27 , 380, 127-31

Congenital long QT syndrome is characterized by a prolongation of ventricular repolarization and recurrent episodes of life-threatening ventricular tachyarrhythmias, often leading to sudden death. We previously identified a missense mutation F275S located within the S5 transmembrane domain of the KCNQ1 ion channel in a Chinese family with long QT syndrome. We used oocyte expression of the KCNQ1 polypeptide to study the effects of the F275S mutation on channel properties. Expression of the F275 mutant, or co-expression with the wild-type S275 polypeptide, significantly decreased channel current amplitudes. Moreover, the F275S substitution decreased the rates of channel activation and deactivation. In transfected HEK293 cells fluorescence microscopy revealed that the F275S mutation perturbed the subcelluar localization of the ion channel. These results indicate that the F275S KCNQ1 mutation leads to impaired polypeptide trafficking that in turn leads to reduction of channel ion currents and altered gating kinetics.