Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome
We identified a single nucleotide variation (SNV) (c.1264A > G) in the KCNQ1 gene in a 5-year-old boy who presented with a prolonged QT interval. His elder brother and mother, but not sister and father, also had this mutation. This missense mutation leads to a p.Lys422Glu (K422E) substitution in...
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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/1422-0067/23/14/7953 |
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| author | Maria Karlova Denis V. Abramochkin Ksenia B. Pustovit Tatiana Nesterova Valery Novoseletsky Gildas Loussouarn Elena Zaklyazminskaya Olga S. Sokolova |
| author_facet | Maria Karlova Denis V. Abramochkin Ksenia B. Pustovit Tatiana Nesterova Valery Novoseletsky Gildas Loussouarn Elena Zaklyazminskaya Olga S. Sokolova |
| author_sort | Maria Karlova |
| collection | DOAJ |
| description | We identified a single nucleotide variation (SNV) (c.1264A > G) in the KCNQ1 gene in a 5-year-old boy who presented with a prolonged QT interval. His elder brother and mother, but not sister and father, also had this mutation. This missense mutation leads to a p.Lys422Glu (K422E) substitution in the Kv7.1 protein that has never been mentioned before. We inserted this substitution in an expression plasmid containing Kv7.1 cDNA and studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1, using the whole-cell configuration of the patch-clamp technique. Expression of the mutant Kv7.1 channel in both homo- and heterozygous conditions in the presence of auxiliary subunit KCNE1 results in a significant decrease in tail current densities compared to the expression of wild-type (WT) Kv7.1 and KCNE1. This study also indicates that K422E point mutation causes a dominant negative effect. The mutation was not associated with a trafficking defect; the mutant channel protein was confirmed to localize at the cell membrane. This mutation disrupts the poly-Lys strip in the proximal part of the highly conserved cytoplasmic A–B linker of Kv7.1 that was not shown before to be crucial for channel functioning. |
| first_indexed | 2024-03-09T13:41:39Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:41:39Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bafdc579680b46fbba31c5977456a6002023-11-30T21:07:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314795310.3390/ijms23147953Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT SyndromeMaria Karlova0Denis V. Abramochkin1Ksenia B. Pustovit2Tatiana Nesterova3Valery Novoseletsky4Gildas Loussouarn5Elena Zaklyazminskaya6Olga S. Sokolova7Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaInstitute of Immunology and Physiology, Ural Branch of Russian Academy of Sciences, 620049 Ekaterinburg, RussiaFaculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaNantes Université, CNRS, INSERM, l’institut du Thorax, F-44000 Nantes, FrancePetrovsky National Research Center of Surgery, 119991 Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaWe identified a single nucleotide variation (SNV) (c.1264A > G) in the KCNQ1 gene in a 5-year-old boy who presented with a prolonged QT interval. His elder brother and mother, but not sister and father, also had this mutation. This missense mutation leads to a p.Lys422Glu (K422E) substitution in the Kv7.1 protein that has never been mentioned before. We inserted this substitution in an expression plasmid containing Kv7.1 cDNA and studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1, using the whole-cell configuration of the patch-clamp technique. Expression of the mutant Kv7.1 channel in both homo- and heterozygous conditions in the presence of auxiliary subunit KCNE1 results in a significant decrease in tail current densities compared to the expression of wild-type (WT) Kv7.1 and KCNE1. This study also indicates that K422E point mutation causes a dominant negative effect. The mutation was not associated with a trafficking defect; the mutant channel protein was confirmed to localize at the cell membrane. This mutation disrupts the poly-Lys strip in the proximal part of the highly conserved cytoplasmic A–B linker of Kv7.1 that was not shown before to be crucial for channel functioning.https://www.mdpi.com/1422-0067/23/14/7953KCNQ1Kv7.1I<sub>Ks</sub>patch-clampinherited channelopathyLQTS |
| spellingShingle | Maria Karlova Denis V. Abramochkin Ksenia B. Pustovit Tatiana Nesterova Valery Novoseletsky Gildas Loussouarn Elena Zaklyazminskaya Olga S. Sokolova Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome International Journal of Molecular Sciences KCNQ1 Kv7.1 I<sub>Ks</sub> patch-clamp inherited channelopathy LQTS |
| title | Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome |
| title_full | Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome |
| title_fullStr | Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome |
| title_full_unstemmed | Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome |
| title_short | Disruption of a Conservative Motif in the C-Terminal Loop of the KCNQ1 Channel Causes LQT Syndrome |
| title_sort | disruption of a conservative motif in the c terminal loop of the kcnq1 channel causes lqt syndrome |
| topic | KCNQ1 Kv7.1 I<sub>Ks</sub> patch-clamp inherited channelopathy LQTS |
| url | https://www.mdpi.com/1422-0067/23/14/7953 |
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