Functional characterization and identification of a therapeutic for a novel SCN5A-F1760C variant causing type 3 long QT syndrome refractory to all guideline-directed therapies
Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain.
OBJECTIVE: The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
METHODS: Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT.
RESULTS: V1/2 of inactivation was right-shifted significantly in F1760C cells (-72.2 ± 0.7 mV) compared to wild-type (WT) cells (-86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P = .0005). Baseline APD to 90% repolarization (APD90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD90, and treatment with 5μM PHT significantly decreased APD90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001).
CONCLUSION: PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site.
| Errataetall: |
CommentIn: Heart Rhythm. 2023 May;20(5):718-719. - PMID 36806575 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Heart rhythm - 20(2023), 5 vom: 01. Mai, Seite 709-717 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Stutzman, Marissa J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.10.2023 Date Revised 28.10.2023 published: Print-Electronic CommentIn: Heart Rhythm. 2023 May;20(5):718-719. - PMID 36806575 Citation Status MEDLINE |
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| doi: |
10.1016/j.hrthm.2023.01.032 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Stutzman, Marissa J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Functional characterization and identification of a therapeutic for a novel SCN5A-F1760C variant causing type 3 long QT syndrome refractory to all guideline-directed therapies |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 28.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Heart Rhythm. 2023 May;20(5):718-719. - PMID 36806575 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain | ||
| 520 | |a OBJECTIVE: The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) | ||
| 520 | |a METHODS: Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT | ||
| 520 | |a RESULTS: V1/2 of inactivation was right-shifted significantly in F1760C cells (-72.2 ± 0.7 mV) compared to wild-type (WT) cells (-86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P = .0005). Baseline APD to 90% repolarization (APD90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD90, and treatment with 5μM PHT significantly decreased APD90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001) | ||
| 520 | |a CONCLUSION: PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site | ||
| 650 | 4 | |a Case Reports | |
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| 650 | 4 | |a Genetic testing | |
| 650 | 4 | |a Induced pluripotent stem cell–derived cardiomyocytes | |
| 650 | 4 | |a Long QT syndrome | |
| 650 | 4 | |a SCN5A | |
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| 700 | 1 | |a Gao, Xiaozhi |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Maengjo |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Tester, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Giudicessi, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Shannon, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Ackerman, Michael J |e verfasserin |4 aut | |
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