Phenotypic and genomic characterization of Becker dystrophy patients with 45 to 55 exons deletion
Elena Gargaun
(1)
,
Rabah Ben Yaou
(1)
,
Marine Guibaud
(1)
,
Guilhem Solé
(2)
,
Vincent Tiffreau
(3)
,
Pascale Laforet
,
Michel Parent
(4)
,
Guillaume Bassez
(5, 6)
,
Catherine Vanhulle
(7)
,
Laurent Servais
(8)
,
Pascal Lacombe
(9)
,
Jean-Michel Pedespan
(10)
,
Adrien Kettaneh
(11)
,
Corinne Roche
(12)
,
Dominique Gaillard
(13)
,
Sabrina Sacconi
(14, 15)
,
Laurence Faivre
(16)
,
Alexandra Nadaj-Pakleza
,
Jean Michel Vallat
(17, 18)
,
Cécile Laroche
(19)
,
Anne-Gaëlle Le Moing
,
Julien Durigneux
(20)
,
Christine Themar-Noel
(21)
,
Marie Laure Negrier
,
Caroline Espil-Taris
(10)
,
Elise Boucher
,
Anne Delaubier
(22)
,
Claire Guillou
(23)
,
Jean Marie Cuisset
,
Andoni Urtizberea
(24)
,
Bruno Eymard
(25)
,
Anne Boland
(26, 27)
,
Jean François Deleuze
(28)
,
David Salgado
(29)
,
Martin Krahn
(30, 31)
,
Nicolas Levy
(31, 32)
,
Alexia Blesius
(33)
,
France Leturcq
(34)
,
France Pietri-Rouxel
(1)
1
Centre de recherche en Myologie – U974 SU-INSERM
2 CRMN - AOC - Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe
3 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
4 Pathologie Nord Unilabs
5 CHU Pitié-Salpêtrière [AP-HP]
6 Institut de Myologie
7 Service de Pédiatrie Néonatale et Réanimation – Neuropédiatrie [CHU Rouen]
8 Service of Clinical Trials and Databases
9 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
10 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
11 Recherche en épidémiologie et biostatistique
12 Service de Neurologie [Vichy]
13 Dynamique cellulaire et moléculaire de la muqueuse respiratoire
14 CHU Nice - Centre Hospitalier Universitaire de Nice
15 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
16 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
17 MMNP - Maintenance Myélinique et Neuropathies Périphériques
18 Service de Neurologie [CHU Limoges]
19 Service de Pédiatrie médicale [CHU Limoges]
20 Pediatric Neurology Department, University Hospital, Ang ers, France,
21 87, avenue Raymond-Poincaré, 75116 Paris
22 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
23 UB - Université de Bordeaux
24 Hôpital Marin
25 Institut de Myologie
26 CNRGH - Centre National de Recherche en Génomique Humaine
27 IG - Institut de Génomique d'Evry
28 Fondation Jean Dausset CEPH
29 AMU - Aix Marseille Université
30 TIMONE - Hôpital de la Timone [CHU - APHM]
31 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
32 Département de génétique médicale [Hôpital de la Timone - APHM]
33 IRIS - Institut de Recherches Internationales Servier [Suresnes]
34 Hôpital Cochin [AP-HP]
2 CRMN - AOC - Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe
3 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
4 Pathologie Nord Unilabs
5 CHU Pitié-Salpêtrière [AP-HP]
6 Institut de Myologie
7 Service de Pédiatrie Néonatale et Réanimation – Neuropédiatrie [CHU Rouen]
8 Service of Clinical Trials and Databases
9 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
10 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
11 Recherche en épidémiologie et biostatistique
12 Service de Neurologie [Vichy]
13 Dynamique cellulaire et moléculaire de la muqueuse respiratoire
14 CHU Nice - Centre Hospitalier Universitaire de Nice
15 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
16 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
17 MMNP - Maintenance Myélinique et Neuropathies Périphériques
18 Service de Neurologie [CHU Limoges]
19 Service de Pédiatrie médicale [CHU Limoges]
20 Pediatric Neurology Department, University Hospital, Ang ers, France,
21 87, avenue Raymond-Poincaré, 75116 Paris
22 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
23 UB - Université de Bordeaux
24 Hôpital Marin
25 Institut de Myologie
26 CNRGH - Centre National de Recherche en Génomique Humaine
27 IG - Institut de Génomique d'Evry
28 Fondation Jean Dausset CEPH
29 AMU - Aix Marseille Université
30 TIMONE - Hôpital de la Timone [CHU - APHM]
31 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
32 Département de génétique médicale [Hôpital de la Timone - APHM]
33 IRIS - Institut de Recherches Internationales Servier [Suresnes]
34 Hôpital Cochin [AP-HP]
Pascale Laforet
- Fonction : Auteur
Alexandra Nadaj-Pakleza
- Fonction : Auteur
Anne-Gaëlle Le Moing
- Fonction : Auteur
- PersonId : 1149763
- ORCID : 0009-0009-8132-6814
- IdRef : 162166338
Marie Laure Negrier
- Fonction : Auteur
Elise Boucher
- Fonction : Auteur
Jean Marie Cuisset
- Fonction : Auteur
Résumé
Becker muscular dystrophy (BMD) is an X linked disorder with 1/30000 life births incidence and is characterized by a progressive muscular dystrophy with or without cardiomyopathy. We present a population of 49 BMD patients with a DMD gene in-phase deletion of exons 45 to 55 (BMDdel45-55). Interestingly, emerging regulatory actors as lncRNA are localized in introns 44 and 55 (Bovolenta et al., 2012). Thus, the specific neo-introns of each patient could create or modify the lncRNA and/or RNA non-coding sequences. The objective of this study is to identify modifier factors involved in phenotypic variability in BMDdel45-55 patients. As described in literature, 63% of Duchenne patients are eligible to a multiexon skipping therapy by skipping exons 45 to 55.
We performed (i) a phenotypic characterization of 49 patients, (ii) a lncRNA profile in 40/49patients and (iii) a WGS in 19/49patients. We have established the profile of lncRNA presence at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52).
In our cohort 22% of patients have dilatative cardiomyopathy, interestingly in 51% the first signs age was <18 y.o. After the cardiac involvement, the most disabling complains are the walking/running difficulties (46 %) and fatigue (34%). With the exception of one outlier there is a strong correlation between the age of the first signs and the presence of cardiomyopathy. We have established lncRNA profile in 38/49 patients. The cluster with the less numbers of lncRNA have a “milder” phenotype. In addition, in Myo-45-52 the profile of lncRNA expression investigated by RT-PCR, underlined two lacking lncRNA.
This study allowed us to describe phenotypic and genomic profile in the largest reported cohort of BMDdel45-55 patients. We identified a cluster with the less numbers of lncRNA with a “milder” phenotype. Genomic data profiling of the candidates for multiexon skipping therapy of 45 to 55 exons would have a favorable contribution in the design of these therapeutic approaches.
Bovolenta, M., Erriquez, D., Valli, E., Brioschi, S., Scotton, C., Neri, M., Falzarano, M.S., Gherardi, S., Fabris, M., Rimessi, P., et al. (2012). The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms. PloS One 7, e45328.