title: Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.
abstract: 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.
authors.affiliation: Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.forename: Long-Mei
authors.initials: LM
authors.lastname: Wu
authors.forename: Natsuko
authors.initials: N
authors.lastname: Inagaki
authors.forename: Takeharu
authors.initials: T
authors.lastname: Hayashi
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Seiko
authors.initials: S
authors.lastname: Kawano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hirano
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: 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
chemical_list: D017931:DNA Primers; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated