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, MBNL1? 101 vector, Jocelyn Laporte (IGBMC

, Wolfson Centre for Neuromuscular Disease, UK), the Research Resource Network of Japan for providing human tissue samples, the Penn Vector Core, Gene Therapy Program, University of Pennsylvania (Philadelphia) for providing the pAAV2/9 plasmid (p5E18-VD29) and all IGBMC common facilities for assistance, Glenn Morris for the gift of the anti MBNL1 and MBNL2 antibodies

, This work was supported by ERC-2012-StG #310659, RNA DISEASES

A. #18833, Animal model for DM, NCB

E. and A. , HEART DM

, INBS-07 PHENOMIN (ICS)

, Research Grants for Practical Research Project for

, Rare / Intractable Diseases and for Comprehensive Research on Persons with Disabilities from AMED (MPT)

M. N. , L. S. , M. N. , T. L. , K. L. et al., Clinical samples and patient data were obtained from A, Aids from JSPS (MPT) and Intramural Research Grant of NCNP 26-8 performed by

G. Rna-sequencing and . Gse85984,

, Left panel, RT-PCR analysis of Atp2a1 (SERCA1) exon 22 inclusion in tibialis anterior muscles of control non-transgenic or HSA LR mice. The percentage of exon 22

, Supplementary figure 4 (related to Figure 5): (A) H&E and NADH-PH staining of mouse tibialis anterior (TA) muscles injected for 1 month with AAV2/9BIN1 isoforms with or without exons 7 and 11. Scale bar = 200 µm. (B) Left panel, muscle fiber area of mouse TA muscles injected for 1 month with AAV2/9-BIN1 isoforms with or without exons 7 and 11. Right panel, quantification of small (< 2600 µm²) versus large (> 3000 µm²) muscle fibers. (C) Percentage of fibers with centrally located nuclei in mouse TA muscles injected for 1 month with AAV2/9-BIN1 isoforms with or without exons 7 and 11. (D to F) Muscle absolute maximal force (D), specific maximal force (E) and fatigue resistance (F) were assessed in situ in mouse TA muscles injected for 1 month with AAV2/9-BIN1 isoforms with or without exons 7 and 11. (G) Left panel, transmission electron microscopy of potassium ferrocyanide stained mouse TA muscles injected for 1 month with AAV2/9-BIN1 isoforms with or without exons 7 and 11. Black arrowheads shows normal T-tubules whereas red arrowheads shows altered T-tubules. Scale bar = 1µm. Right panel, quantification of normal and abnormal T-tubules. For all experiments, Molecular sizes are indicated in base pairs on the left of the gel. Right panel, quantification of the percentage of Atp2a1 mRNA including its exon 22. Bars indicate s.e.m with n=4 different mice in each groups. Student's t-test, *** indicates P < 0.0001, vol.127

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, Rôle de l'inclusion de l'exon 7 de BIN1 dans la faiblesse

, est une maladie génétique héréditaire affectant environ 1/8000 personnes. Les patients souffrant de DM1 développent essentiellement des troubles musculaires tels qu'une faiblesse et une atrophie musculaire. La cause de la DM1 est expliquée par la mutation du gène

, En effet, l'exon 7 de BIN1, qui est absent du muscle normal, est exprimé de façon aberrante chez les patients DM1. En utilisant un modèle murin, j'ai prouvé que l'expression forcée de l'exon 7 de BIN1 altérait simultanément la structure et la fonction du muscle. Nous avons notamment observés une diminution de la taille des fibres musculaires et une augmentation de la faiblesse musculaire, comparé à des souris normales. Par conséquent, ce travail aidera à la compréhension du mécanisme de la maladie et

, Mots clés : BIN1 ; DNM2 ; dystrophie myotonique de type 1 ; DM1 ; ARN ; épissage alternatif ; AAV ; faiblesse musculaire