Paradoxically, gain-of-function mutations in KCNQ1 have been reported to cause borderline QT prolongation, atrial fibrillation (AF), sinus bradycardia, and sudden death, however, the mechanisms are not well understood.
In patients followed from birth to 60 years of age, patients with LQT3 had an increased risk of AF compared with genotype-negative family members (hazard ratio=6.62; 95% CI, 2.04-21.49; <i>P</i><0.001), while neither LQT1 nor LQT2 demonstrated increased AF risk.
Hasegawa et al reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential duration (APD) in atrial cells.
We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early-onset lone AF (<40 years) and investigated the identified mutations functionally in a heterologous expression system.
Functional analysis has shown that the missense gain-in-function KCNQ1S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I(Ks)).
Two mutations (S140G and V141M) that cause familial atrial fibrillation (AF) are located on adjacent residues in the first membrane-spanning domain of KCNQ1, S1.
Among 231 participants in the Vanderbilt AF Registry, we found a mutation in KCNQ1 (encoding the alpha-subunit of slow delayed rectifier potassium current [I(Ks)]) and separately a mutation in natriuretic peptide precursor A (NPPA) gene (encoding atrial natriuretic peptide, ANP), both segregating with early onset lone AF in different kindreds.
We identified a family with lone AF due to a mutation in the highly conserved S3 domain of KCNQ1, a region of the channel not previously implicated in the pathogenesis of AF.
Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1.
Five (2.4%) of 211 patients with LQT1-susceptibility mutations had documented AF, compared to 0 of 174 patients with LQT2, 1 of 59 patients with LQT3, 1 of 1 patient with Andersen-Tawil syndrome, and 1 of 34 patients with multiple mutations.