Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome

Qiuming Gong, David R. Keeney, Jeffrey C. Robinson, Zhengfeng Zhou

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Mutations in the human ether-a-go-go-related gene (HERG) cause long QT syndrome type 2 (LQT2). HERG encodes a voltage-gated potassium channel consisting of four subunits. Tetrameric assembly is required for the formation of functional HERG channels. In the present work, we studied the role of assembly in HERG channel dysfunction of LQT2 mutations Q725X and R1014X, both of which cause truncations of the C-terminus of HERG channels. When expressed in HEK293 cells, Q725X did not generate HERG current, while R1014X generated HERG current with markedly reduced amplitude. Western blot analysis showed that both mutations caused defective trafficking of HERG channel proteins. Using sucrose gradient centrifugation we showed that wild type HERG and R1014X formed a tetrameric structure, whereas Q725X was expressed as a monomer. When coexpressed with wild type HERG, R1014X, but not Q725X, caused dominant negative suppression of wild type HERG current. Coimmunoprecipitation experiments showed that the lack of dominant negative effect by Q725X was due to failure of mutant subunits to coassemble with wild type subunits. These results suggest that the Q725X mutation causes HERG channel dysfunction by disruption of tetrameric assembly of HERG channels. In contrast, the R1014X mutation is capable of forming tetrameric structure, and it causes HERG channel dysfunction by defective trafficking of the mutant protein.

Original languageEnglish (US)
Pages (from-to)1225-1233
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number6
DOIs
StatePublished - Dec 2004
Externally publishedYes

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Human Trafficking
Long QT Syndrome
Ether
Genes
Mutation
Voltage-Gated Potassium Channels
HEK293 Cells

Keywords

  • Arrhythmia
  • Ion channels
  • Mutations
  • Patch clamp
  • Protein trafficking

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome. / Gong, Qiuming; Keeney, David R.; Robinson, Jeffrey C.; Zhou, Zhengfeng.

In: Journal of Molecular and Cellular Cardiology, Vol. 37, No. 6, 12.2004, p. 1225-1233.

Research output: Contribution to journalArticle

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