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

Yoshiyasu Aizawa, Kazuo Ueda, Long-Mei Wu, Natsuko Inagaki, Takeharu Hayashi, Megumi Takahashi, Masaaki Ohta, Seiko Kawano, Yuji Hirano, Michio Yasunami, Yoshifusa Aizawa, Akinori Kimura, Masayasu Hiraoka

FEBS Lett., 2004 Sep 10 , 574, 145-50

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.