De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.
OBJECTIVE
We describe a genetic basis for atrial fibrillation and short QT syndrome in utero. Heterologous expression of the mutant channel was used to define the physiological consequences of the mutation.


METHODS
A baby girl was born at 38 weeks after induction of delivery that was prompted by bradycardia and irregular rythm. ECG revealed atrial fibrillation with slow ventricular response and short QT interval. Genetic analysis identified a de novo missense mutation in the potassium channel KCNQ1 (V141M). To characterize the physiological consequences of the V141M mutation, Xenopus laevis oocytes were injected with cRNA encoding wild-type (wt) KCNQ1 or mutant V141M KCNQ1 subunits, with or without KCNE1.


RESULTS
Ionic currents were recorded using standard two-microelectrode voltage clamp techniques. In the absence of KCNE1, wtKCNQ1 and V141M KCNQ1 currents had similar biophysical properties. Coexpression of wtKCNQ1+KCNE1 subunits induced the typical slowly activating and voltage-dependent delayed rectifier K(+) current, I(Ks). In contrast, oocytes injected with cRNA encoding V141M KCNQ1+KCNE1 subunits exhibited an instantaneous and voltage-independent K(+)-selective current. Coexpression of V141M and wtKCNQ1 with KCNE1 induced a current with intermediate biophysical properties. Computer modeling showed that the mutation would shorten action potential duration of human ventricular myocytes and abolish pacemaker activity of the sinoatrial node.


CONCLUSIONS
The description of a novel, de novo gain of function mutation in KCNQ1, responsible for atrial fibrillation and short QT syndrome in utero indicates that some of these cases may have a genetic basis and confirms a previous hypothesis that gain of function mutations in KCNQ1 channels can shorten the duration of ventricular and atrial action potentials.
Hong
Kui
K
Masonic Medical Research Laboratory, Utica, NY, USA.
Piper
David R
DR
Diaz-Valdecantos
Aurora
A
Brugada
Josep
J
Oliva
Antonio
A
Burashnikov
Elena
E
Santos-de-Soto
José
J
Grueso-Montero
Josefina
J
Diaz-Enfante
Ernesto
E
Brugada
Pedro
P
Sachse
Frank
F
Sanguinetti
Michael C
MC
Brugada
Ramon
R
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D005315:Fetal Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009865:Oocytes; D011247:Pregnancy; D012849:Sinoatrial Node / Q000502:physiology; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis
D051657:KCNQ1 Potassium Channel