title: Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model.
abstract: BACKGROUND
  Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 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.
  
  
  RESULTS
  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< or = 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(v)1.5 mRNA but higher Na(v)1.5 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.
  
  
  CONCLUSIONS
  Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression.
authors.affiliation: INSERM, UMR915, l'Institut du Thorax, Nantes, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leoni
authors.forename: Bruno
authors.initials: B
authors.lastname: Gavillet
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.forename: Céline
authors.initials: C
authors.lastname: Marionneau
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Christopher L H
authors.initials: CL
authors.lastname: Huang
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western; D053840:Brugada Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D019683:Penetrance; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels