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 Ca2+ 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.
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Acknowledgments
We are greatly indebted to the patients. We thank Dr Alexandre Duparc (Pôle cardiovasculaire et Métabolique de Cardiologie B, Hôpital de Rangueil, Toulouse, France), Stéphanie Chatel and Christine Fruchet for assistance in the family recruitment; Estelle Baron, Stéphanie Bonnaud, Laëtitia Duboscq-Bidot, Béatrice Leray, and Aurore Girardeau for technical assistance; Jean-Baptiste Chéron for his help in action potential modelling; and Philippe Hulin at Imaging Core Facility (MicroPICell, SFR François Bonamy, University of Nantes) for expert technical assistance with FRAP. We are also grateful to the Genomic Platform of Nantes (Biogenouest Genomics) for technical support, to Raluca Teusan and Pierre Lindenbaum for the bioinformatics support and to Anne Ponchaux, Jerome Buscail, Thierry Marsaud, Prof Stéphane Bézieau (Service de génétique médicale, Nantes) for their assistance in SCN5A sequencing. We are also grateful to the referral centre against inherited cardiac arrhythmias of Nantes and Rennes. This work was supported by the Leducq Foundation [CVD-05; Alliance Against Sudden Cardiac Death]; and by the French Ministry of Health (P.H.R.C.I. DGS2001/0248).
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D. M. Béziau and J. Barc are contributed equally to this work.
J.-J. Schott, V. Probst and I. Baró authors jointly directed this work.
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Béziau, D.M., Barc, J., O’Hara, T. et al. Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations. Basic Res Cardiol 109, 446 (2014). https://doi.org/10.1007/s00395-014-0446-5
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DOI: https://doi.org/10.1007/s00395-014-0446-5