Functional analysis of a double-point mutation in the KCNJ2 gene identified in a family with Andersen-Tawil syndrome

Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy with autosomal dominant inheritance resulting in periodic paralysis, arrhythmia characterized by QT prolongation, and dysmorphic features. The KCNJ2 gene has been identified as the causative gene of ATS. Herein, we reported 2 cases of a 21-year-old man and his mother, with episodic paralytic attacks and/or arrhythmia, which are characteristic of ATS. Both G144A, a reported ATS mutation, and V296F, a novel mutation, were identified in the KCNJ2 gene on the same allele from the proband and his mother, but not from his father. In the present study, we investigated the functional effect of these variants on the potassium channel Kir2.1 and the significance of the double mutation. G144A, V296F, and G144A-V296F mutant channels expressed in cultured cells revealed a loss-of-function effect of these mutations on Kir2.1. The K⁺ currents of G144A and G144A-V296F channels were more suppressed than that of V296F channel alone, whereas was no difference between G144A and G144A-V296F. To our knowledge, a double mutation in the KCNJ2 gene has not been reported previously. While either of 2 mutations potentially causes ATS, the G144A mutation might cause the dominant effect on the patients' clinical presentation.