RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue European Heart Journal Année : 2019

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

Zeina Al Sayed
  • Fonction : Auteur
Laurence Jesel
  • Fonction : Auteur
Hongchao Guo
  • Fonction : Auteur
Haodi Wu
  • Fonction : Auteur
Christophe Guilluy
  • Fonction : Auteur
Florian Simonet
  • Fonction : Auteur
Sabine Pattier
  • Fonction : Auteur
Carol Scott
  • Fonction : Auteur
Carol Chariau
  • Fonction : Auteur
Anne Gaignerie
  • Fonction : Auteur
Emmanuelle Génin
Jean-François Deleuze
  • Fonction : Auteur
  • PersonId : 1015006
Joseph Wu
  • Fonction : Auteur

Résumé

Aims : The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation. Methods and results : Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude. Conclusion : This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.

Dates et versions

inserm-02158572 , version 1 (18-06-2019)

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Citer

Nadjet Belbachir, Vincent Portero, Zeina Al Sayed, Jean-Baptiste Gourraud, Florian Dilasser, et al.. RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome. European Heart Journal, 2019, ⟨10.1093/eurheartj/ehz308⟩. ⟨inserm-02158572⟩
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