Dr. Zhao and Dr. Hill contributed equally to this work.
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 Phenotype
Article first published online: 10 APR 2009
© 2009 Wiley Periodicals, Inc.
Journal of Cardiovascular Electrophysiology
Volume 20, Issue 8, pages 923–930, August 2009
How to Cite
ZHAO, J. T., HILL, A. P., VARGHESE, A., COOPER, A. A., SWAN, H., LAITINEN-FORSBLOM, P. J., REES, M. I., SKINNER, J. R., CAMPBELL, T. J. and VANDENBERG, J. I. (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 Phenotype. Journal of Cardiovascular Electrophysiology, 20: 923–930. doi: 10.1111/j.1540-8167.2009.01468.x
This work was supported in part by grants from the St. Vincent's Clinic Foundation (to TJC), the National Heart Foundation of Australia (GIA G06S2585 to JIV, JRS, and MIR), and the National Health and Medical Research Council (NHMRC 459402, 573715 to JIV). APH is supported by a NHFA post-doctoral fellowship (Gxxxxxxx). JIV is supported by an NHMRC Senior Research Fellowship (NHMRC 459401). JRS and MIR are supported by Cure Kids of New Zealand and the Green Lane Trust.
- Issue published online: 28 JUL 2009
- Article first published online: 10 APR 2009
- Manuscript received 17 December 2008; Revised manuscript received 2 February 2009; Accepted for publication 9 February 2009.
- long-QT syndrome;
- protein trafficking;
- kinetic modeling;
- human ether-a-go-go-related gene
Introduction: Mutations in the pore domain of the human ether-a-go-go-related gene (hERG) potassium channel are associated with higher risk of sudden death. However, in many kindreds clinical presentation is variable, making it hard to predict risk. We hypothesized that in vitro phenotyping of the intrinsic severity of individual mutations can assist with risk stratification.
Methods and Results: We analyzed 2 hERG pore domain mutations, G572S and G584S. Similar to 90% of hERG missense mutations, G572S-hERG subunits did not traffic to the plasma membrane but could coassemble with WT subunits and resulted in a dominant negative suppression of hERG current density. The G584S-hERG subunits traffic normally but have abnormal inactivation gating. Computer models of human ventricular myocyte action potentials (AP), incorporating Markov models of the hERG mutants, indicate that G572S-hERG channels would cause more severe AP prolongation than that seen with G584S-hERG channels.
Conclusions: hERG-G572S and -G584S are 2 pore domain mutations that involve the same change in sidechain but have very different in vitro phenotypes; G572S causes a dominant negative trafficking defect, whereas G584S is the first hERG missense mutation where the cause of disease can be exclusively attributed to enhanced inactivation. The G572S mutation is intrinsically more severe than the G584S mutation, consistent with the overall clinical presentation in the 2 small kindreds studied here. Further investigation, involving a larger number of cohorts, to test the hypothesis that in vitro phenotyping of the intrinsic severity of a given mutation will assist with risk stratification is therefore warranted.