V141M (SQTS)

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CLINICAL FINDINGS AND IN VITRO EXPRESSION

The article by Hing 2005 et al. paper reports on a case of atrial fibrillation that was diagnosed in utero. utero, with concomitant bradycardia, a short QT interval and a structurally normal heart. Pregnancy was interrupted at 38 weeks due to severe fetal bradycardia and irregular rhythm, suggesting AF, detected since the 6th month of gestation.

Genetic analysis revealed a point mutation (V141M) in KCNQ1. Val141 is adjacent to Ser140,the residue mutated in the large family with AF and long QT syndrome previously reported. The electrophysiological phenotype of the V141M is overall similar to that previously described for the S140G mutation: a gain of function caused by a loss of voltage dependent channel gating when co-expressed with KCNE1. .The V141M mutant channel is able to conduct outward current in a wide voltage range (from -80mV up to -30mV) with an almost straight current-voltage relationship. However, the I-V relationship of the WT+V141M (+KCNE1) co-expression (to simulate heterozygous condition), produced currents were more similar to WT.

In silico numerical simulations with the myocyte model showed unaltered resting potential, marginal changes of the peak voltage, but significant differences between wt and the mutation for action potential duration. The peak voltage decreased from 23 mV in wt to 21 mV in wt/V141M. Action potential duration at 90% repolarization(APD90) decreased from 314 ms in wt myocytes to 283 ms(9.9%) in wt/V141M myocytes.