Variable Na.sub.v1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a.sup.+/- Mouse Model

• Published in: PloS one Vol. 5; no. 2; p. e9298
• Main Authors: Leoni, Anne-Laure, Gavillet, Bruno, Rougier, Jean-Sébastien, Marionneau, Céline, Probst, Vincent, Le Scouarnec, Solena, Schott, Jean-Jacques, Demolombe, Sophie, Bruneval, Patrick, Huang, Christopher L. H, Colledge, William H, Grace, Andrew A, Le Marec, Hervé, Wilde, Arthur A, Mohler, Peter J, Escande, Denis, Abriel, Hugues, Charpentier, Flavien
• Format: Journal Article
• Language: English
• Published: Public Library of Science 19.02.2010
• Subjects: Comparative analysis; Electrocardiography; Genetic aspects; Medical research; Tachycardia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009298

Loss-of-function mutations in SCN5A, the gene encoding Na.sub.v 1.5 Na.sup.+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a.sup.+/- mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. Based on ECG, 10-week-old Scn5a.sup.+/- mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS[less than or equal to]18 ms; QRS in wild-type littermates: 10-18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na.sup.+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a.sup.+/- mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a.sup.+/- mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a.sup.+/- mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a.sup.+/- mice had similar Na.sub.v 1.5 mRNA but higher Na.sub.v 1.5 protein expression, and moderately larger I.sub.Na current than severely affected Scn5a.sup.+/- mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a.sup.+/- mice than in mildly affected ones. Scn5a.sup.+/- mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a.sup.+/- mice, phenotype severity correlates with wild-type Na.sub.v 1.5 protein expression.