Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes
The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jerv...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/13/7389 |
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| author | Peter M. Kekenes-Huskey Don E. Burgess Bin Sun Daniel C. Bartos Ezekiel R. Rozmus Corey L. Anderson Craig T. January Lee L. Eckhardt Brian P. Delisle |
| author_facet | Peter M. Kekenes-Huskey Don E. Burgess Bin Sun Daniel C. Bartos Ezekiel R. Rozmus Corey L. Anderson Craig T. January Lee L. Eckhardt Brian P. Delisle |
| author_sort | Peter M. Kekenes-Huskey |
| collection | DOAJ |
| description | The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano–Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in <i>KCNQ1</i> (LQT1) and <i>KCNH2</i> (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different <i>KCNQ1</i> and <i>KCNH2</i> missense variants and discuss gene- and mutation-specific differences in K<sup>+</sup> channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of <i>KCNQ1</i> and <i>KCNH2</i> variants, with the goal of realizing a layered precision medicine approach focused on individuals. |
| first_indexed | 2024-03-09T21:48:18Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:48:18Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b854c6681c334712a3b75b03eb578b772023-11-23T20:12:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012313738910.3390/ijms23137389Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome PhenotypesPeter M. Kekenes-Huskey0Don E. Burgess1Bin Sun2Daniel C. Bartos3Ezekiel R. Rozmus4Corey L. Anderson5Craig T. January6Lee L. Eckhardt7Brian P. Delisle8Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USADepartment of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology, Harbin Medical University, Harbin 150081, ChinaAgios Pharmaceuticals, Cambridge, MA 02139, USADepartment of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USACellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USACellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USACellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USAThe electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano–Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in <i>KCNQ1</i> (LQT1) and <i>KCNH2</i> (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different <i>KCNQ1</i> and <i>KCNH2</i> missense variants and discuss gene- and mutation-specific differences in K<sup>+</sup> channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of <i>KCNQ1</i> and <i>KCNH2</i> variants, with the goal of realizing a layered precision medicine approach focused on individuals.https://www.mdpi.com/1422-0067/23/13/7389long QT syndrome<i>KCNQ1</i><i>KCNH2</i>K<sup>+</sup> channelheartarrhythmia |
| spellingShingle | Peter M. Kekenes-Huskey Don E. Burgess Bin Sun Daniel C. Bartos Ezekiel R. Rozmus Corey L. Anderson Craig T. January Lee L. Eckhardt Brian P. Delisle Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes International Journal of Molecular Sciences long QT syndrome <i>KCNQ1</i> <i>KCNH2</i> K<sup>+</sup> channel heart arrhythmia |
| title | Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes |
| title_full | Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes |
| title_fullStr | Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes |
| title_full_unstemmed | Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes |
| title_short | Mutation-Specific Differences in Kv7.1 (<i>KCNQ1</i>) and Kv11.1 (<i>KCNH2</i>) Channel Dysfunction and Long QT Syndrome Phenotypes |
| title_sort | mutation specific differences in kv7 1 i kcnq1 i and kv11 1 i kcnh2 i channel dysfunction and long qt syndrome phenotypes |
| topic | long QT syndrome <i>KCNQ1</i> <i>KCNH2</i> K<sup>+</sup> channel heart arrhythmia |
| url | https://www.mdpi.com/1422-0067/23/13/7389 |
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