title: A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome.
abstract: BACKGROUND
  Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and life-threatening polymorphic ventricular tachyarrhythmias. LQT1 caused by KCNQ1 mutations is the most common form of LQTS.
  
  
  RESULTS
  Patients diagnosed with LQTS were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and SCN5A. A novel mutation was identified in KCNQ1 caused by a three-base deletion at the position 824-826, predicting a deletion of phenylalanine at codon 275 in segment 5 of KCNQ1 (DeltaF275). Wild-type (WT) and DeltaF275-KCNQ1 constructs were generated and transiently transfected together with a KCNE1 construct in CHO-K1 cells to characterize the properties of the slowly activating delayed rectifier current (IKs) using conventional whole-cell patch-clamp techniques. Cells transfected with WT-KCNQ1 and KCNE1 (1:1.3 molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail current density measured at -40 mV following a two-second step to +60 mV was 381.3 +/- 62.6 pA/pF (n = 11). Cells transfected with DeltaF275-KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8 +/- 2.1 pA/pF, n = 11, P = 0.00001 vs WT). Cotransfection of WT- and DeltaF275- KCNQ1 (50/50), along with KCNE1, produced little to no current (tail current density: 10.3 +/- 3.5 pA/pF, n = 11, P = 0.00001 vs WT alone), suggesting a potent dominant negative effect. Immunohistochemistry showed normal membrane trafficking of DeltaF275-KCNQ1.
  
  
  CONCLUSIONS
  Our data suggest that a DeltaF275 mutation in KCNQ1 is associated with a very potent dominant negative effect leading to an almost complete loss of function of IKs and that this defect underlies a LQT1 form of LQTS.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.forename: Fabiana
authors.initials: F
authors.lastname: Scornik
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Mayurika
authors.initials: M
authors.lastname: Desai
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Nagata
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Iesaka
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000293:Adolescent; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000145:classification* / Q000235:genetics / Q000503:physiopathology*
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human