Loss-of-function mutations in SCN5A, the gene encoding Na_v1.5 Na⁺ 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^+/− mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A.

Based on ECG, 10-week-old Scn5a^+/− mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS≤18 ms; QRS in wild-type littermates: 10–18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na⁺ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a^+/− 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^+/− 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^+/− mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a^+/− mice had similar Na_v1.5 mRNA but higher Na_v1.5 protein expression, and moderately larger I_Na current than severely affected Scn5a^+/− mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a^+/− mice than in mildly affected ones.

Scn5a^+/− mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a^+/− mice, phenotype severity correlates with wild-type Na_v1.5 protein expression.