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.
Aizawa
Yoshiyasu
Y
Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Ueda
Kazuo
K
Wu
Long-Mei
LM
Inagaki
Natsuko
N
Hayashi
Takeharu
T
Takahashi
Megumi
M
Ohta
Masaaki
M
Kawano
Seiko
S
Hirano
Yuji
Y
Yasunami
Michio
M
Aizawa
Yoshifusa
Y
Kimura
Akinori
A
Hiraoka
Masayasu
M
D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D018613:Microscopy, Confocal; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D021381:Protein Transport
D017931:DNA Primers; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated