Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome

Corey L. Anderson, Catherine E. Kuzmicki, Ryan R. Childs, Caleb J. Hintz, Brian P. Delisle, Craig T. January

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

It has been suggested that deficient protein trafficking to the cell membrane is the dominant mechanism associated with type 2 Long QT syndrome (LQT2) caused by Kv11.1 potassium channel missense mutations, and that for many mutations the trafficking defect can be corrected pharmacologically. However, this inference was based on expression of a small number of Kv11.1 mutations. We performed a comprehensive analysis of 167 LQT2-linked missense mutations in four Kv11.1 structural domains and found that deficient protein trafficking is the dominant mechanism for all domains except for the distal carboxy-terminus. Also, most pore mutations - in contrast to intracellular domain mutations - were found to have severe dominant-negative effects when co-expressed with wild-type subunits. Finally, pharmacological correction of the trafficking defect in homomeric mutant channels was possible for mutations within all structural domains. However, pharmacological correction is dramatically improved for pore mutants when co-expressed with wild-type subunits to form heteromeric channels.

Original languageEnglish
Article number5535
JournalNature Communications
Volume5
DOIs
StatePublished - 2014

Bibliographical note

Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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