A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome.
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.
Aizawa
Yoshiyasu
Y
Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA.
Ueda
Kazuo
K
Scornik
Fabiana
F
Cordeiro
Jonathan M
JM
Wu
Yuesheng
Y
Desai
Mayurika
M
Guerchicoff
Alejandra
A
Nagata
Yasutoshi
Y
Iesaka
Yoshito
Y
Kimura
Akinori
A
Hiraoka
Masayasu
M
Antzelevitch
Charles
C
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*
D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human