Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness
<i>KCNQ1</i> encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current <i>I</i><sub>Ks</sub>, which...
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2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/3/1112 |
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| author | Annemarie Oertli Susanne Rinné Robin Moss Stefan Kääb Gunnar Seemann Britt-Maria Beckmann Niels Decher |
| author_facet | Annemarie Oertli Susanne Rinné Robin Moss Stefan Kääb Gunnar Seemann Britt-Maria Beckmann Niels Decher |
| author_sort | Annemarie Oertli |
| collection | DOAJ |
| description | <i>KCNQ1</i> encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current <i>I</i><sub>Ks</sub>, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in <i>KCNQ1</i> cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in <i>KCNQ1</i> result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous <i>KCNQ1</i> mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in <i>Xenopus laevis</i> oocytes, are in agreement with an autosomal recessive disorder, since the <i>I</i><sub>Ks</sub> reduction was only observed in homomeric mutants, but not in heteromeric <i>I</i><sub>Ks</sub> channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant <i>I</i><sub>Ks</sub> channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment. |
| first_indexed | 2024-03-09T03:53:50Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T03:53:50Z |
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| spelling | doaj.art-d3e4a3ef7b4840b993bf83c1b951cb2f2023-12-03T14:23:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-01223111210.3390/ijms22031112Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without DeafnessAnnemarie Oertli0Susanne Rinné1Robin Moss2Stefan Kääb3Gunnar Seemann4Britt-Maria Beckmann5Niels Decher6Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, GermanyInstitute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, GermanyInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg–Bad Krozingen, Medical Center-University of Freiburg, 79110 Freiburg, GermanyDepartment of Medicine I, University Hospital, LMU Munich, 80336 Munich, GermanyInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg–Bad Krozingen, Medical Center-University of Freiburg, 79110 Freiburg, GermanyDepartment of Medicine I, University Hospital, LMU Munich, 80336 Munich, GermanyInstitute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, Germany<i>KCNQ1</i> encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current <i>I</i><sub>Ks</sub>, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in <i>KCNQ1</i> cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in <i>KCNQ1</i> result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous <i>KCNQ1</i> mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in <i>Xenopus laevis</i> oocytes, are in agreement with an autosomal recessive disorder, since the <i>I</i><sub>Ks</sub> reduction was only observed in homomeric mutants, but not in heteromeric <i>I</i><sub>Ks</sub> channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant <i>I</i><sub>Ks</sub> channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.https://www.mdpi.com/1422-0067/22/3/1112KCNQ1LQTSpotassium channelelectrophysiology |
| spellingShingle | Annemarie Oertli Susanne Rinné Robin Moss Stefan Kääb Gunnar Seemann Britt-Maria Beckmann Niels Decher Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness International Journal of Molecular Sciences KCNQ1 LQTS potassium channel electrophysiology |
| title | Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness |
| title_full | Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness |
| title_fullStr | Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness |
| title_full_unstemmed | Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness |
| title_short | Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness |
| title_sort | molecular mechanism of autosomal recessive long qt syndrome 1 without deafness |
| topic | KCNQ1 LQTS potassium channel electrophysiology |
| url | https://www.mdpi.com/1422-0067/22/3/1112 |
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