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

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103 Scopus citations


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
StatePublished - 2014

Bibliographical note

Funding Information:
We thank Dr Jennifer Poehls in the Dept. of Medicine and Dr Krishanu Saha in the Dept. of Biomedical Engineering at UW-Madison for helpful suggestions. We thank Dr Michael Ackerman (Mayo Clinic) for sharing pre-publication genotype information. This study was supported by the NIH R01 HL060723 (C.T.J.), an AHA Midwest Affiliate Predoctoral Fellowship (C.L.A.), a grant from the Saving tiny Hearts Society (B.P.D.) and a NIH training grant T32 HL07936 (Dr Jonathan C. Makielski).

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

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)


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