<i>SCN5A</i>‐C683R exhibits combined gain‐of‐function and loss‐of‐function properties related to adrenaline‐triggered ventricular arrhythmia
Notice bibliographique
Résumé
New Findings What is the role of SCN5A‐C683R? SCN5A ‐C683R is a novel variant associated with an uncommon phenotype of adrenaline‐triggered ventricular arrhythmia in the absence of a distinct ECG phenotype. What is the main finding and its importance? Functional studies demonstrated that Na V 1.5/C683R results in a mixed electrophysiological phenotype with gain‐of‐function (GOF) and loss‐of‐function (LOF) properties compared with Na V 1.5/wild type. Gain‐of‐function properties are characterized by a significant increase of the maximal current density and a hyperpolarizing shift of the steady‐state activation. The LOF effect of Na V 1.5/C683R is characterized by increased closed‐state inactivation. Electrophysiological properties and clinical manifestation of SCN5A ‐C683R are different from long‐QT‐3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome. Abstract Mutations of SCN5A have been identified as the genetic substrate of various inherited arrhythmia syndromes, including long‐QT‐3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline‐triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A ‐C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of Na V 1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site‐directed mutagenesis. Na V 1.5/wild type (WT) and Na V 1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole‐cell patch‐clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8‐CPT‐cAMP. The impact of β‐blockers was tested by exposing Na V 1.5/WT and Na V 1.5/C683R currents to propranolol and nadolol. C683R resulted in a co‐association of gain‐of‐function and loss‐of‐function properties of Na V 1.5. Gain‐of‐function properties were characterized by a significant increase of the maximal Na V 1.5 current density compared with Na V 1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in Na V 1.5/C683R with 8‐CPT‐cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady‐state activation (−65.4 ± 3.0 vs. −57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss‐of‐function effect of Na V 1.5/C683R was characterized by significantly increased closed‐state inactivation compared with Na V 1.5/WT ( P < 0.05). C683R is a novel SCN5A variant resulting in a co‐association of gain‐of‐function and loss‐of‐function properties of the cardiac sodium channel Na V 1.5. The phenotype is characterized by adrenaline‐triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long‐QT‐3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».