In a female infant with short QT interval, atrial fibrillation, and bradycardia (SQT2; 609621), Hong et al. (2005) identified heterozygosity for a c.421G-A transition in the KCNQ1 gene, resulting in a val141-to-met (V141M) substitution within transmembrane domain S1. Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel.
In 2 unrelated girls with short QT syndrome, AF, and bradycardia, Villafane et al. (2014) identified heterozygosity for the V141M mutation in the KCNQ1 gene.
Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (176261), Peng et al. (2017) characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, ser140 to gly (S140G; 607542.0032) and V141M. In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation.
