title: Congenital long QT syndrome caused by the F275S KCNQ1 mutation: mechanism of impaired channel function.
abstract: 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.
authors.affiliation: Department of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Qiu-fen
authors.initials: QF
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Du
authors.forename: Qiu-Mei
authors.initials: QM
authors.lastname: Xu
authors.forename: Qin-Mei
authors.initials: QM
authors.lastname: Ke
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Xue-Lin
authors.initials: XL
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.forename: Shou-Yan
authors.initials: SY
authors.lastname: Zhang
authors.forename: Cai-Lian
authors.initials: CL
authors.lastname: Kang
authors.forename: Si-Ming
authors.initials: SM
authors.lastname: Guan
authors.forename: Jun-Guo
authors.initials: JG
authors.lastname: Yang
authors.forename: Zi-Fang
authors.initials: ZF
authors.lastname: Song
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D012694:Serine; D010649:Phenylalanine