title: De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.
abstract: 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.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Hong
authors.forename: David R
authors.initials: DR
authors.lastname: Piper
authors.forename: Aurora
authors.initials: A
authors.lastname: Diaz-Valdecantos
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliva
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: José
authors.initials: J
authors.lastname: Santos-de-Soto
authors.forename: Josefina
authors.initials: J
authors.lastname: Grueso-Montero
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Enfante
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Frank
authors.initials: F
authors.lastname: Sachse
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: 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
chemical_list: D051657:KCNQ1 Potassium Channel