Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants
The <i>KCNQ1</i> gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current <i>I</i...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1350 |
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| author | Susanne Rinné Annemarie Oertli Claudia Nagel Philipp Tomsits Tina Jenewein Stefan Kääb Silke Kauferstein Axel Loewe Britt Maria Beckmann Niels Decher |
| author_facet | Susanne Rinné Annemarie Oertli Claudia Nagel Philipp Tomsits Tina Jenewein Stefan Kääb Silke Kauferstein Axel Loewe Britt Maria Beckmann Niels Decher |
| author_sort | Susanne Rinné |
| collection | DOAJ |
| description | The <i>KCNQ1</i> gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current <i>I</i><sub>Ks</sub>, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in <i>KCNQ1</i> cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in <i>KCNQ1</i> result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel <i>KCNQ1</i> variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the <i>KCNQ1</i> gene. We functionally characterized nine human <i>KCNQ1</i> variants using the voltage-clamp technique in <i>Xenopus laevis</i> oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with <i>in silico</i> modelling approaches are valuable components for the interpretation of the pathogenicity of <i>KCNQ1</i> variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score. |
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| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-756cf7ea2a0e4900a17133d511bd2adf2023-11-30T22:39:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242135010.3390/ijms24021350Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> VariantsSusanne Rinné0Annemarie Oertli1Claudia Nagel2Philipp Tomsits3Tina Jenewein4Stefan Kääb5Silke Kauferstein6Axel Loewe7Britt Maria Beckmann8Niels Decher9Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, GermanyInstitute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, GermanyInstitute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, GermanyDepartment of Medicine I, University Hospital, LMU Munich, 80802 Munich, GermanyInstitute of Legal Medicine, Goethe University, University Hospital Frankfurt, 60590 Frankfurt, GermanyDepartment of Medicine I, University Hospital, LMU Munich, 80802 Munich, GermanyInstitute of Legal Medicine, Goethe University, University Hospital Frankfurt, 60590 Frankfurt, GermanyInstitute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, GermanyDepartment of Medicine I, University Hospital, LMU Munich, 80802 Munich, GermanyInstitute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, GermanyThe <i>KCNQ1</i> gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current <i>I</i><sub>Ks</sub>, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in <i>KCNQ1</i> cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in <i>KCNQ1</i> result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel <i>KCNQ1</i> variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the <i>KCNQ1</i> gene. We functionally characterized nine human <i>KCNQ1</i> variants using the voltage-clamp technique in <i>Xenopus laevis</i> oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with <i>in silico</i> modelling approaches are valuable components for the interpretation of the pathogenicity of <i>KCNQ1</i> variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.https://www.mdpi.com/1422-0067/24/2/1350potassium channelKCNQ1KvLQT1LQTSRomano-Ward syndrome |
| spellingShingle | Susanne Rinné Annemarie Oertli Claudia Nagel Philipp Tomsits Tina Jenewein Stefan Kääb Silke Kauferstein Axel Loewe Britt Maria Beckmann Niels Decher Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants International Journal of Molecular Sciences potassium channel KCNQ1 KvLQT1 LQTS Romano-Ward syndrome |
| title | Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants |
| title_full | Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants |
| title_fullStr | Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants |
| title_full_unstemmed | Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants |
| title_short | Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome <i>KCNQ1</i> Variants |
| title_sort | functional characterization of a spectrum of novel romano ward syndrome i kcnq1 i variants |
| topic | potassium channel KCNQ1 KvLQT1 LQTS Romano-Ward syndrome |
| url | https://www.mdpi.com/1422-0067/24/2/1350 |
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