Truncated KCNQ1 mutant, A178fs/105, forms hetero‐multimer channel with wild‐type causing a dominant‐negative suppression due to trafficking defect

We identified a novel mutation Ala178fs/105 missing S3–S6 and C‐terminus portions of KCNQ1 channel. Ala178fs/105‐KCNQ1 expressed in COS‐7 cells demonstrated no current expression. Co‐expression with wild‐type (WT) revealed a dominant‐negative effect, which suggests the formation of hetero‐multimer by mutant and WT. Confocal laser microscopy displayed intracellular retention of Ala178fs/105‐KCNQ1 protein. Co‐expression of the mutant and WT also increased intracellular retention of channel protein compared to WT alone. Our findings suggest a novel mechanism for LQT1 that the truncated S1–S2 KCNQ1 mutant forms hetero‐multimer and cause a dominant‐negative effect due to trafficking defect.