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
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 mous...
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Published in | PloS one Vol. 5; no. 2; p. e9298 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Public Library of Science
19.02.2010
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0009298 |