Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome
Open Access
- 24 November 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 5 (1), 1-13
- https://doi.org/10.1038/ncomms6535
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.Keywords
This publication has 70 references indexed in Scilit:
- Genotype-Phenotype Aspects of Type 2 Long QT SyndromeJournal of the American College of Cardiology, 2009
- Absence of Direct Cyclic Nucleotide Modulation of mEAG1 and hERG1 Channels Revealed with Fluorescence and Electrophysiological MethodsPublished by Elsevier BV ,2009
- A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channelsProceedings of the National Academy of Sciences of the United States of America, 2009
- Not All hERG Pore Domain Mutations Have a Severe Phenotype: G584S Has an Inactivation Gating Defect with Mild Phenotype Compared to G572S, Which Has a Dominant Negative Trafficking Defect and a Severe PhenotypeJournal of Cardiovascular Electrophysiology, 2009
- A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophreniaNature Medicine, 2009
- Role of intracellular domains in the function of the herg potassium channelEuropean Biophysics Journal, 2009
- Identification of a possible pathogenic link between congenital long QT syndrome and epilepsyNeurology, 2009
- The G604S-hERG mutation alters the biophysical properties and exerts a dominant-negative effect on expression of hERG channels in HEK293 cellsPflügers Archiv - European Journal of Physiology, 2008
- Single mutations convert an outward K + channel into an inward K + channelProceedings of the National Academy of Sciences of the United States of America, 2008
- Molecular code for transmembrane-helix recognition by the Sec61 transloconNature, 2007