Phenotypic Manifestations of Val93Ile Missense Mutation and Its Influence on Kir2.1 Channel Functioning

Abstract For the first time, a patient with asymptomatic QT interval prolongation was found to carry missense mutation c.277G>A (p.Val93Ile) in the KCNJ2 gene, described previously only as the cause of a familial form of atrial fibrillation. The corresponding amino acid substitution was introduced into the plasmid encoding the Kir2.1 channel and the mutant gene was expressed in Chinese hamster ovary cells (CHO-K1) to evaluate the effect of the mutation on I K1 current parameters. Using the whole-cell patch-clamp technique in the voltage clamp mode, the integral I K1 current was studied. The results revealed that the c.277G>A (p.Val93Ile) mutation is implemented according to the gain-of-function type and significantly changes the functioning of the Kir 2.1 channel. The presence of a stable activating effect on protein function argues in favor of the clinical significance of the identified variant.