title: Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations.
abstract: Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of sudden cardiac death. We have recently reported families with BrS and SCN5A mutations where some affected members do not carry the familial mutation. We evaluated the involvement of additional genetic determinants for BrS in an affected family. We identified three distinct gene variants within a family presenting BrS (5 individuals), cardiac conduction defects (CCD, 3 individuals) and shortened QT interval (4 individuals). The first mutation is nonsense, p.Q1695*, lying within the SCN5A gene, which encodes for NaV1.5, the α-subunit of the cardiac Na(+) channel. The second mutation is missense, p.N300D, and alters the CACNA1C gene, which encodes the α-subunit CaV1.2 of the L-type cardiac Ca(2+) channel. The SCN5A mutation strictly segregates with CCD. Four out of the 5 BrS patients carry the CACNA1C variant, and three of them present shortened QT interval. One of the BrS patients carries none of these mutations but a rare variant located in the ABCC9 gene as well as his asymptomatic mother. Patch-clamp studies identified a loss-of-function of the mutated CaV1.2 channel. Western-blot experiments showed a global expression defect while increased mobility of CaV1.2 channels on cell surface was revealed by FRAP experiments. Finally, computer simulations of the two mutations recapitulated patient phenotypes. We report a rare CACNA1C mutation as causing BrS and/or shortened QT interval in a family also carrying a SCN5A stop mutation, but which does not segregate with BrS. This study underlies the complexity of BrS inheritance and its pre-symptomatic genetic screening interpretation.
authors.affiliation: INSERM, UMR 1087, l'institut du thorax, 8 Quai Moncousu, BP 70721, 44007, Nantes cedex 1, France.
authors.forename: Delphine M
authors.initials: DM
authors.lastname: Béziau
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hara
authors.forename: Laurianne
authors.initials: L
authors.lastname: Le Gloan
authors.forename: Mohamed Yassine
authors.initials: MY
authors.lastname: Amarouch
authors.forename: Aude
authors.initials: A
authors.lastname: Solnon
authors.forename: Dominique
authors.initials: D
authors.lastname: Pavin
authors.forename: Simon
authors.initials: S
authors.lastname: Lecointe
authors.forename: Patricia
authors.initials: P
authors.lastname: Bouillet
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gourraud
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Philippe
authors.initials: P
authors.lastname: Mabo
authors.forename: Hervé
authors.initials: H
authors.lastname: le Marec
authors.forename: Gildas
authors.initials: G
authors.lastname: Loussouarn
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baró
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics*; D019556:COS Cells; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human