Ecole doctorale "LOGIQUE DU VIVANT - ED 515

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Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Nom et prénom du directeur de thèse (et si besoin du co-directeur) : GUICHENEY Pascale
Le directeur de thèse et le co-directeur doivent impérativement être habilités à diriger les recherches (HDR)
Coordonnées
Tel : 01.40.77.98.05
e-mail : [email protected]
Nom et prénom du co-encadrant (non HdR ) (s’il y a lieu) :
Coordonnées Tel :
e-mail :
Nom et prénom du responsable de l’équipe : TREGOUET David-Alexandre
Nombre de chercheurs et enseignants-chercheurs statutaires de l’équipe titulaires d’une HDR : 4
Nom et prénom du responsable du laboratoire : HATEM Stéphane
Intitulé du laboratoire et N° d’unité : UMRS 1166
Spécialité : Génétique, Biologie cellulaire
Titre du projet de thèse :
Genome edition of a cardiomyocyte cell line to study mutations in new genes causing lifethreatening arrhythmias
Résumé du projet de thèse (1 page maximum, en anglais)
Cardiac sudden deaths are due to ventricular tachycardia (VT) degenerating into ventricular
fibrillation and asystole. In a small percentage of patients without structural heart disease, such lifethreatening arrhythmias are due to ion-channel dysfunction caused by mutations in ion channels or
associated proteins. Among these primary electrophysiological disorders, also called channelopathies,
more than twenty genes have been discovered as being responsible for long QT syndrome, Brugada
syndrome, catecholaminergic polymorphic VT and short QT syndrome. For these diseases, ECG
abnormalities are present either on the basal ECG or are revealed by exercise or a drug challenge test.
In contrast, there are patients with no ECG abnormalities, but with life-threatening arrhythmias which
are thus called idiopathic ventricular fibrillation (IVF). They form probably a heterogeneous group, all
with implanted defibrillator to prevent sudden death, poorly explored on a genetic and
pathophysiological point of view.
We performed exome sequencing in a subgroup of 20 well-characterized symptomatic IVF patients,
who present VF with short-coupled premature ventricular beat (PVB) or Torsade de pointes (TdP)
originating from Purkinje fibers. The TdP is a distinct polymorphic ventricular tachycardia appearing as
a twist around the isoelectric line. The short-coupled torsades de pointes (scTdP) were reported as a
new electrocardiographic entity in 1994 among patients with normal ECG at basal level (1). All the
patients were young adults of both genders. The coupling interval of TdP was very short (200 to 300
ms), in contrast to the long coupling interval of the classical form of TdP (600 to 800 ms) registered in
long QT syndrome patients (2,3). The genetic origin of this rare entity is suggested by the occurrence of
familial sudden deaths and dominant transmission in some families, even if the majority of the living
patients are sporadic cases. Since treatment by verapamil, a calcium antagonist, can prevent
arrhythmias in these patients, a calcium dysregulation is expected.
Our analysis of the exome data did not reveal a unique gene but several missense variants especially
in calcium channel subunits but also in partners of the ion channel complexes. Our working hypothesis
is that such primary rhythm disorders leading to SCD display complex genetic inheritance with the
involvement of multiple variants of different effect sizes in different genes.
1
Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
We need to explore the function of new variants of interest, so far not known to be involved in
cardiac sudden death. We will introduce these variants in a cell line of murine cardiomyocytes, HL1, by
genome edition using the CRISPR/Cas9 technology (4). Such a model is more appropriate than mutated
plasmid overexpression to study the alteration of structural and scaffolding proteins on the localization,
trafficking to the membrane and function of calcium channels and calcium induced calcium release.
Our team owns the skills necessary the realization of this project. Positive results will open a door for
the comprehension of the much larger group of IVF patients in the future.
1. Leenhardt A, Glaser E, Burguera M, Nürnberg M, Maison-Blanche P, Coumel P. Short-coupled variant of
torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular
tachyarrhythmias. Circulation 1994, 89 : 206-215.
2. Haïssaguerre M, Shoda M, Jaïs P, Nogami A, Shah DC, Kautzner J, Arentz T, Kalushe D, Lamaison D,
Griffith M, Cruz F, de Paola A, Gaïta F, Hocini M, Garrigue S, Macle L, Weerasooriya R, Clémenty J.
Mapping and ablation of idiopathic ventricular fibrillation. Circulation 2002, 106:962-967.
3. Chiladadis JA, Spiroulias G, Koutsogiannis N, Zagli F, Alexopoulos D. Short-coupled variant of torsade de
pointes as a cause of electrical storm and aborted sudden cardiac death: insights into mechanism and
treatment. Hellenic J. Cardiol. 2008, 49: 360-364.
4. Sander JD, Joung JK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nature
Biotechnology, 2014, 32 : 347-355.
Thèses actuellement en cours dans l’équipe
Nom et Prénom du doctorant
Malorie BLANCARD (ED515)
Romain CHARMET (ED393)
Anne-Sophie PULCRANO
(ED393)
Myriam FERNANDES
BENARBA (ED515)
Nom du directeur de thèse
Guicheney Pascale
David-Alexandre
Trégouet
David-Alexandre
Trégouet
Eric Villard
Année de 1ere
inscription et
Ecole Doctorale
Financement pendant la thèse
Oct 2014
Oct 2014
Bourse Ministère Handicap
Allocation doctorale CORDDIM
Oct 2015
Bourse Ministère
Oct 2015
Bourse CIFRE
Trois publications récentes du directeur de thèse (du co-directeur ou du co-encadrant s’il y a lieu).Mettre en gras le nom
du directeur de thèse.
Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T,
Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W,
Guicheney P*, Schwartz PJ*, Horie M*.
The genetics underlying acquired long QT syndrome: impact for genetic screening.
Eur Heart J. 2015 Dec 28. [Epub ahead of print] *contributed equally as senior authors.
Itoh H, Berthet M, Fressart V, Denjoy I, Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Stallmeyer B,
Zumhagen S, Shimizu W, Wilde AA, Schulze-Bahr E, Horie M, Tezenas du Montcel S, Guicheney P.
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to
channel dysfunction.
Eur Heart J. 2015 Dec 28. [Epub ahead of print]
Ziyadeh-Isleem A*, Clatot J*, Duchatelet S, Gandjbakhch E, Denjoy I, Hidden-Lucet F, Hatem S, Deschênes I, Coulombe
A, Neyroud N, Guicheney P. A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome
and early atrial fibrillation. Heart Rhythm 2014;11: 1015-23.
Docteurs encadrés par le directeur de thèse ayant soutenu après septembre 2010 et publications relatives à leur sujet de thèse.
Mettre en gras le nom du directeur de thèse et celui du docteur.
2
Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Nom Prénom : ZIYADEH-ISLEEM Azza
Date de soutenance : 4 avril 2014
Durée de thèse (en mois): 43 mois
Ecole Doctorale : 515
Publications :
Clatot J, Ziyadeh-Isleem A, Maugenre S, Denjoy I, Liu H, Dilanian G, Hatem SN, Deschênes I, Coulombe A,
Guicheney P*, Neyroud N*. Dominant-negative effect of SCN5A N-terminal mutations through the interaction of
Nav1.5 alpha-subunits. Cardiovasc Res 2012, 96: 53-63.
Shevchuk AI, Novak P, Taylor M, Diakonov IA, Ziyadeh-Isleem A, Bitoun M, Guicheney P, Lab MJ, Gorelik
J, Merrifield CJ, Klenerman D, Korchev YE. An alternative mechanism of clathrin coated pit closure revealed by ion
conductance microscopy. J Cell Biol. 2012, 197: 499-508.
Ziyadeh-Isleem A*, Clatot J*, Duchatelet S, Gandjbakhch E, Denjoy I, Hidden-Lucet F, Hatem S, Deschênes
I, Coulombe A, Neyroud N, Guicheney P. A truncating SCN5A mutation combined with genetic variability causes sick
sinus syndrome and early atrial fibrillation. Heart Rhythm 2014, 11: 1015-23.
Nom Prénom : KATTYGNARATH Darouna
Date de soutenance : 5 juillet 2013
Durée de thèse (en mois): 34 mois
Ecole Doctorale : ED515
Publications :
Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C, Denjoy I, Dilanian G, Martins RP, Fressart V,
Berthet M, Schott JJ, Leenhardt A, Probst V, Le Marec H, Hainque B, Coulombe A, Hatem SN, Guicheney P. MOG1:
a new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet. 2011;4: 4:261-8.
Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C, Denjoy I, Dilanian G, Martins Rp, Fressart V,
Berthet M, Schott Jj, Leenhardt A, Probst V, Le Marec H, Hainque B, Coulombe A, Hatem Sn, Guicheney P.
Response to the letter of Olesen et al Circ Cardiovasc Genet. 2011 Oct 1;4(5):e23.
Duthoit G, Fressart V, Hidden-Lucet F, Simon F, Kattygnarath D, Charron P, Himbert C, Aouate P,
Guicheney P, Lecarpentier Y, Frank R, Hébert JL. Brugada ECG pattern: a physiopathological prospective study based
on clinical, electrophysiological, angiographic and genetic findings. Front Physiol. 2012; 3:474.
Nom Prénom : CLATOT Jérome
Date de soutenance : 29 mars 2012
Durée de thèse (en mois): 38 mois
Ecole Doctorale : ED515
Publications :
Clatot J, Ziyadeh-Isleem A, Maugenre S, Denjoy I, Liu H, Dilanian G, Hatem SN, Deschênes I, Coulombe A,
Guicheney P*, Neyroud N*. Dominant-negative effect of SCN5A N-terminal mutations through the interaction of
Nav1.5 alpha-subunits. Cardiovasc Res 2012, 96: 53-63.
Ziyadeh-Isleem A*, Clatot J*, Duchatelet S, Gandjbakhch E, Denjoy I, Hidden-Lucet F, Hatem S, Deschênes
I, Coulombe A, Neyroud N, Guicheney P. A truncating SCN5A mutation combined with genetic variability causes sick
sinus syndrome and early atrial fibrillation. Heart Rhythm 2014, 11: 1015-23.
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