F. Charpentier, M. De Waard, I. Baró, G. Loussouarn, M. Ronjat, JB. Gourraud, P. Lemarchand, N. Gaborit, J. Montnach, M. Derangeon, G. Toumaniantz

 

This program is mainly focused on the study of genetically-inherited cardiac arrhythmic diseases, in close collaboration with team I and the Reference Centre for Hereditary or Rare Cardiac Rhythm Disorders from Nantes University Hospital. This program is built around 4 main projects.
 

Pathophysiological mechanisms of Brugada syndrome

Following our previous studies, we will investigate the pathophysiological mechanisms of Brugada syndrome related to the p.R211H mutation in RRAD gene, using a knock-in mouse model carrying the equivalent mutation and induced pluripotent stem cell-derived cardiomyocyte (iPSC-CMs).

CRISPR/Cas9-based genome editing in human iPSC-CMs will also be used to investigate the functional effects of common genetic variants identified by team I in non-coding regions as increasing the risk of Brugada syndrome.
 

Modelling other inherited arrhythmic disorders with human iPSC

We further aim to contribute to the characterization of the functional impact of the genetic variants that alter cardiac excitability in humans. Recently, a de novo gene variant has been identified by team I in two unrelated patients affected by the newly described generalized ST-segment depression syndrome. The cellular and molecular mechanisms of this disease is currently investigated in iPSC-CMs from one patient and isogenic cell lines.

Finally, we aim at performing cellular characterization of the catecholamine-induced QT prolongation syndrome we have recently described. The affected patients present with a prolongation of their QT interval only under adrenergic stimulation, and more specifically under mental stress. So far, genetic studies have failed to identify a culprit gene. We will perform transcriptomic and electrophysiological studies of iPSC-CMs from unrelated affected patients in basal and under stress (isoproterenol) conditions. If successful, this work may pioneer future studies on mechanistically and genetically unresolved diseases.
 

Functional consequences of gene variants identified in Constances cohort

In collaboration with Team I, Team II will contribute to the Inserm Transversal Program in genomic variability (GOLD). We have generated human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background to test the functional consequences of gene variants in coding and non-coding regions identified in Constances individuals in the field of cardiac arrythmias, more specifically J-wave syndromes, cardiac conduction diseases and atrial fibrillation
 

High-throughput characterization of the impact of genetic variation on cardiac ion channels

The acquisition of a high-throughput automated patch-clamp setup allow us to characterize rare genetic variants affecting the ion channels involved in cardiac rhythm defects. While the phenotypic characterization of these increasingly reported variants is lagging behind significantly, this effort is important in a translational context, in order to better interpret genetic findings in the context of molecular diagnosis and help patient counselling in the perspective of personalized medicine. In this context, we have initiated the high-throughput characterization of coding variants in the hERG channel (KCNH2 gene) to determine their involvement in long QT syndrome type 2.

Publications


A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity. Oliveira-Mendes B, Feliciangeli S, Ménard M, Chatelain F, Alameh M, Montnach J, Nicolas S, Ollivier B, Barc J, Baró I, Schott JJ, Probst V, Kyndt F, Denjoy I, Lesage F, Loussouarn G, De Waard M. Clin Transl Med 2021;11(11): e609

A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype. Al Sayed ZR, Jouni M, Gourraud JB, Belbachir N, Barc J, Girardeau A, Forest V, Derevier A, Gaignerie A, Chariau C, Cimarosti B, Canac R, Olchesqui P, Charpentier E, Schott JJ, Redon R, Baró I, Probst V, Charpentier F, Loussouarn G, Zibara K, Lamirault G, Lemarchand P, Gaborit N. Clin Transl Med 2021; 11: e413

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome. Belbachir N*, Portero V*, Reda Al Sayed Z, Gourraud JB, Dilasser F, Jesel L, Guo H, Wu H, Gaborit N, Guilluy C, Girardeau A, Bonnaud S, Simonet F, Karakachoff M, Pattier S, Scott C, Burel S, Marionneau C, Chariau C, Gaignerie A, David L, Genin E, Deleuze JF, Dina C, Sauzeau V, Loirand G, Baró I, Schott JJ, Probst V, Wu JC, Redon R#, Charpentier F#, Le Scouarnec S#. Eur Heart J 2019; 40: 3081-3094. equal contribution as first author; #equal contribution as senior author

Arrhythmias precede cardiomyopathy and remodeling of Ca(2+) handling proteins in a novel model of long QT syndrome. Montnach J*, Chizelle FF*, Belbachir N, Castro C, Li L, Loussouarn G, Toumaniantz G, Carcouët A, Meinzinger AJ, Shmerling D, Benitah JP, Gómez AM, Charpentier F, Baró I. J Mol Cell Cardiol 2018; 23: 13-25. *equal contribution as first author; #equal contribution as senior author

Familial Catecholamine-Induced QT Prolongation in Unexplained Sudden Cardiac Death. Huchet F, Kyndt F, Barc J, Thollet A, Charpentier F, Redon R, Schott JJ, Le Marec H, Probst V, Gourraud JB. J Am Coll Cardiol 2017; 69(12): 1642-1643