Fiche Projet

Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Nom et prénom du directeur de thèse (et si besoin du co-directeur) : Laurent Servais
Le directeur de thèse et le co-directeur doivent impérativement être habilités à diriger les recherches (HDR) Laurent Servais
Coordonnées
Tel : 01 44 73 65 44
e-mail : [email protected]
Nom et prénom du co-directeur: Piétri-Rouxel France
Coordonnées
Tel : 01 40 77 96 31
e-mail : [email protected]
Nom et prénom du responsable de l’équipe : Denis Furling
Nombre de chercheurs et enseignants-chercheurs statutaires de l’équipe titulaires d’une HDR : 4
Nom et prénom du responsable du laboratoire : Butler-Browne Gillian
Intitulé du laboratoire et N° d’unité : Centre de Recherche en Myologie, UMRS974 UPMC - INSERM / FRE 3617 CNRS / AIM
Spécialité : Génétique
Titre du projet de thèse : Heterogeneity of the Becker disease severity: involvement of intronic
rearrangements, polymorphism and modulator genes?
Résumé du projet de thèse (1 page maximum, en anglais)
Background
Mutations in DMD disrupting the reading frame prevent dystrophin production and result in Duchenne
muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted
dystrophin and result in the reputed less severe Becker muscular dystrophy (BMD).
BMD45-55 Becker patients display in frame deletion of exons 45 to 55 in the DMD gene. While they all express
a normal level of shortened dystrophin (Dys), they exhibit a phenotypic status ranging from asymptomatic to
severe
The aim of the project is the understanding of the phenotypic heterogeneity of BMD45-55 patients.
Among the consequences of the 44 to 55 exon deletion, one is the alteration of the binding site of the
neuronal nitric oxide synthase (nNOS) to the dystrophin. Indeed, this site is partly deleted in the truncateddystrophin expressed by the BMD45-55 patients. Interestingly, a study carried out on these patients showed a
wide spectrum of nNOS protein expression and localization and its mislocalization was found to be correlated
with increased severity of the clinical and histopathological muscle features (Gentil et al., 2012). However, the
question of the difference in nNOS expression and location between BMD45-55 patients is not elucidated.
Another consequence of the 45 to 55 exon deletion in the DMD gene is the result of breaks in introns 44 and
55 that leads to the creation of a neo-intron composed of the remaining part of intron 44 flanked by the
remaining part of intron 55. The resulting sequence of the neo-intron depends on the breakpoint positions and
could be different for each patient. Knowing that this new sequence could lead to the loss and/or the creation
of important regulated sequences, it is an important interest to precisely characterize the breaking point
sequence for each patient.
A third investigation will track the expression of modifier genes. The data collected from a whole genome
sequencing (WGS) will provide the opportunity to evaluate the polymorphism of genes that could act as
modifier factors of the severity of the phenotype, such as genes related to lipid metabolism; anabolic and
catabolic pathways and hypoxia.
Taking into account the knowledge described above, the assumptions made for the understanding of the
heterogeneity of BMD45-55 patients phenotypes are:
1/The interactions of Dystrophin and its partner nNOS would be differentially affected regarding the single-
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Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
nucleotide non-synonymous polymorphism (SNP) of the DMD and NOS1 genes.
2/The resulting neo-sequence, caused by the deletion of the 44 and 55 exons, contains known (and may yet
unknown) sequences of non-coding RNA (ncRNA) and/or target sequences of ncRNA which could be modified
by the deletion and differently from patient to patient.
3/The variability of the phenotype would be attributed to the expression of modifier factors that could
impact on the pathophysiological process in affected muscles.
To investigate these assumptions, we will carry out a whole genome sequencing (WGS) that will allow
(i) establishing a double cartography of the Dys/nNOS binding site taking into account the polymorphism
in DMD and NOS1 genes
(ii) identifying breakpoints in introns 44 and 55 that could impact on the non-coding RNA identified in this
zone
(iii) identifying modulator genes that could be link to the worsening (or the improvement) of the phenotype
of BMD patients.
Thèses actuellement en cours dans l’équipe
Nom et Prénom du doctorant
Nom du directeur de thèse
Année de 1ere
inscription
Financement pendant la thèse
Le-Moing Anne-Gaëlle
Servais Laurent
2012
CHU Amiens
Damily De Dea Diniz
Magdalena Matloka
Furling
Furling
2014
2015
UPMC
DIM-Biothérapie
Pauline Roy
Ferry
2016
AIM
*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.
Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy.
Hogrel JY, Wary C, Moraux A, Azzabou N, Decostre V, Ollivier G, Canal A, Lilien C, Ledoux I, Annoussamy M, Reguiba N,
Gidaro T, Le Moing AG, Cardas R, Voit T, Carlier PG, Servais L.
Neurology. 2016 Feb 17.
Upper limb strength and function changes during a one-year follow-up in non-ambulant patients with Duchenne Muscular
Dystrophy: an observational multicenter trial.
Seferian AM, Moraux A, Annoussamy M, Canal A, Decostre V, Diebate O, Le Moing AG, Gidaro T, Deconinck N, Van Parys
F, Vereecke W, Wittevrongel S, Mayer M, Maincent K, Desguerre I, Thémar-Noël C, Cuisset JM, Tiffreau V, Denis S, Jousten
V, Quijano-Roy S, Voit T, Hogrel JY, Servais L.
PLoS One. 2015 Feb 2;10(2):e0113999
Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in
Duchenne patients.
Le Guiner C, Montus M, Servais L, Cherel Y, Francois V, Thibaud JL, Wary C, Matot B, Larcher T, Guigand L, Dutilleul M,
Domenger C, Allais M, Beuvin M, Moraux A, Le Duff J, Devaux M, Jaulin N, Guilbaud M, Latournerie V, Veron P, Boutin S,
Leborgne C, Desgue D, Deschamps JY, Moullec S, Fromes Y, Vulin A, Smith RH, Laroudie N, Barnay-Toutain F, Rivière C,
Bucher S, Le TH, Delaunay N, Gasmi M, Kotin RM, Bonne G, Adjali O, Masurier C, Hogrel JY, Carlier P, Moullier P, Voit T.
Mol Ther. 2014 Nov;22(11):1923-35.
Docteurs encadrés par le directeur de thèse ayant soutenu après septembre 2008 et publications relatives à leur sujet de thèse.
Mettre en gras le nom du directeur de thèse et celui du docteur.
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