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

• Published in: FEBS letters 2004-09, Vol.574 (1), p.145-150
• Main Authors: Aizawa, Yoshiyasu, Ueda, Kazuo, Wu, Long-mei, Inagaki, Natsuko, Hayashi, Takeharu, Takahashi, Megumi, Ohta, Masaaki, Kawano, Seiko, Hirano, Yuji, Yasunami, Michio, Aizawa, Yoshifusa, Kimura, Akinori, Hiraoka, Masayasu
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Base Sequence; cDNA, complementary deoxyribonucleic acid; CFP, cyan fluorescent protein; COS Cells; DNA Primers; DNA, deoxyribonucleic acid; ECG, electrocardiogram; Electrophysiology; Female; Frameshift mutation; Genes, Dominant; Humans; KCNQ Potassium Channels; KCNQ1 (KvLQT1); KCNQ1 Potassium Channel; LQT1, long QT syndrome type 1; LQTS, long QT syndrome; Membrane trafficking; Microscopy, Confocal; PCR, polymerase chain reaction; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Protein Transport; S.E.M., standard error of mean; SSCP, single-strand conformation polymorphism; Sudden cardiac death; WT, wild-type; YFP, yellow fluorescent protein
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2004.08.018

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.