Repeat Expansions & Myotonic Dystrophy (REDs)
Our research focuses primarily on Myotonic Dystrophy, one of the most frequent neuromuscular diseases in adults. More specifically, our work is mainly concentrated on Myotonic Dystrophy type 1 (DM1), also known as Steinert disease. DM1 is characterised by progressive muscle weakness and atrophy, myotonia, heart conduction defects, cataracts, endocrine and gastrointestinal problems, as well as neurological manifestations. There are five clinical forms of this multisystemic disease, including late-onset, adult, juvenile, infantile and congenital forms. Currently, there is no treatment for this debilitating genetic disorder, but some therapeutic approaches are currently being developed.
DM1 is an autosomal dominant disease caused by the abnormal expansion of a CTG trinucleotide repeat (n>40) located in the 3′ non-coding region of the DMPK gene. The expanded CTG repeat sequence is highly unstable, further increasing in size not only in different tissues throughout the patient’s life, but also between successive generations. The expansion-biased intergenerational instability of the CTG repeat provides the molecular explanation for the anticipation phenomenon typical of this disease. DM1 is an RNA gain-of-function disease. Expanded DMPK transcripts containing pathological CUG repeats (RNA-CUGexp) are retained in the cell nucleus as riboprotein aggregates (foci) and disrupt the function of important RNA binding proteins (RBPs). In particular, RNA foci sequester RBPs of the MBNL family which are involved in RNA processing and maturation. Thus, the functional loss of MBNL activity leads to alternative splicing defects in a subset of RNA transcripts, which have been associated with key disease symptoms: the abnormal splicing of CLCN1 contributes to myotonia, INSR to insulin resistance, BIN1 to muscle weakness, DMD to altered muscle fibre architecture and SCN5A to defects in cardiac conduction and arrhythmias. However, additional mechanisms operating in various tissues and cell types are involved in the complex pathophysiology of this disease.
The REDs research team was created in 2019, following the merge of the teams of Geneviève Gourdon and Denis Furling. It also includes the group of Guillaume Bassez, a neurologist who coordinates the French Myotonic Dystrophy national registry (DM-Scope); and Arnaud Ferry’s group that focuses on muscle physiology and exercise. The aim of this new multidisciplinary team is to synergise efforts in order accelerate translational research for this neuromuscular disease, with the ultimate aim of offering novel and efficient therapeutic alternatives to patients. To this end, our team carries out integrated research on multiple aspects of DM1, from gene mutation to disease symptoms and the development of new therapeutic strategies. Our projects cover the fundamental mechanisms CTG repeat instability, the understanding of the pathophysiological mechanisms of disease using cellular and animal models, the development and assessment of innovative therapeutic approaches and, finally, the setting up of pre-clinical and clinical trials for DM1.
- Mechanisms of trinucleotide repeat instability in DM1 families, cell and mouse models.
- Molecular and pathophysiological consequences of CTG expansions in the central nervous system and in the congenital form of the disease.
- Preclinical therapeutic assays in DM1 mice, through the assessment of molecular and physiological phenotypes in muscle and CNS.
- Pathophysiological mechanisms triggered by the expression of CUGexp-RNA and the resulting changes in the motor unit and muscular function, as well as in other non-muscular manifestations (e.g. cardiovascular…).
- Development and evaluation of innovative therapeutic approaches for DM1 using cell and mouse models of the disease
- Impact of neuromuscular disease on muscle function and performance (i.e., characterisation of mouse models). Effects of exercise.
- Evaluation of therapeutic approaches on muscle function. Preclinical studies in mouse models, in collaboration with the UMS28 Phenotyping Platform (S. Morosan and M. Lemaitre).
- Integrated physiology of skeletal muscle.
- Phenotypic characterisation and natural history of Myotonic Dystrophy.
- Validation of measurement tools and readouts for clinical trials.
- Coordination of the French Observatory of Myotonic Dystrophies (DM-Scope).
- Moulay, G, Lainé, J, Lemaître, M, Nakamori, M, Nishino, I, Caillol, G et al.. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques. J Cell Biol. 2020;219 (9):. doi: 10.1083/jcb.201912061. PubMed PMID:32642759 PubMed Central PMC7480091.
- Klein, AF, Varela, MA, Arandel, L, Holland, A, Naouar, N, Arzumanov, A et al.. Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J Clin Invest. 2019;129 (11):4739-4744. doi: 10.1172/JCI128205. PubMed PMID:31479430 PubMed Central PMC6819114.
- Lo Scrudato, M, Poulard, K, Sourd, C, Tomé, S, Klein, AF, Corre, G et al.. Genome Editing of Expanded CTG Repeats within the Human DMPK Gene Reduces Nuclear RNA Foci in the Muscle of DM1 Mice. Mol Ther. 2019;27 (8):1372-1388. doi: 10.1016/j.ymthe.2019.05.021. PubMed PMID:31253581 PubMed Central PMC6697452.
- De Antonio, M, Dogan, C, Daidj, F, Eymard, B, Puymirat, J, Mathieu, J et al.. The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care. Orphanet J Rare Dis. 2019;14 (1):122. doi: 10.1186/s13023-019-1088-3. PubMed PMID:31159885 PubMed Central PMC6547518.
- Lagrue, E, Dogan, C, De Antonio, M, Audic, F, Bach, N, Barnerias, C et al.. A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management. Neurology. 2019;92 (8):e852-e865. doi: 10.1212/WNL.0000000000006948. PubMed PMID:30659139 .
- Bassez, G, Audureau, E, Hogrel, JY, Arrouasse, R, Baghdoyan, S, Bhugaloo, H et al.. Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial. Brain. 2018;141 (10):2855-2865. doi: 10.1093/brain/awy231. PubMed PMID:30169600 .
- Delacroix, C, Hyzewicz, J, Lemaitre, M, Friguet, B, Li, Z, Klein, A et al.. Improvement of Dystrophic Muscle Fragility by Short-Term Voluntary Exercise through Activation of Calcineurin Pathway in mdx Mice. Am J Pathol. 2018;188 (11):2662-2673. doi: 10.1016/j.ajpath.2018.07.015. PubMed PMID:30142334 .
- Okkersen, K, Jimenez-Moreno, C, Wenninger, S, Daidj, F, Glennon, J, Cumming, S et al.. Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial. Lancet Neurol. 2018;17 (8):671-680. doi: 10.1016/S1474-4422(18)30203-5. PubMed PMID:29934199 .
- Tomé, S, Dandelot, E, Dogan, C, Bertrand, A, Geneviève, D, Péréon, Y et al.. Unusual association of a unique CAG interruption in 5' of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism. Hum Mutat. 2018;39 (7):970-982. doi: 10.1002/humu.23531. PubMed PMID:29664219 .
- Sicot, G, Servais, L, Dinca, DM, Leroy, A, Prigogine, C, Medja, F et al.. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy. Cell Rep. 2017;19 (13):2718-2729. doi: 10.1016/j.celrep.2017.06.006. PubMed PMID:28658620 PubMed Central PMC8496958.
- Jauvin, D, Chrétien, J, Pandey, SK, Martineau, L, Revillod, L, Bassez, G et al.. Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice. Mol Ther Nucleic Acids. 2017;7 :465-474. doi: 10.1016/j.omtn.2017.05.007. PubMed PMID:28624222 PubMed Central PMC5453865.
- Ueberschlag-Pitiot, V, Stantzou, A, Messéant, J, Lemaitre, M, Owens, DJ, Noirez, P et al.. Gonad-related factors promote muscle performance gain during postnatal development in male and female mice. Am J Physiol Endocrinol Metab. 2017;313 (1):E12-E25. doi: 10.1152/ajpendo.00446.2016. PubMed PMID:28351832 .
- Arandel, L, Polay Espinoza, M, Matloka, M, Bazinet, A, De Dea Diniz, D, Naouar, N et al.. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds. Dis Model Mech. 2017;10 (4):487-497. doi: 10.1242/dmm.027367. PubMed PMID:28188264 PubMed Central PMC5399563.
- De Antonio, M, Dogan, C, Hamroun, D, Mati, M, Zerrouki, S, Eymard, B et al.. Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification. Rev Neurol (Paris). 2016;172 (10):572-580. doi: 10.1016/j.neurol.2016.08.003. PubMed PMID:27665240 .
- Roy, P, Rau, F, Ochala, J, Messéant, J, Fraysse, B, Lainé, J et al.. Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle. Skelet Muscle. 2016;6 :23. doi: 10.1186/s13395-016-0096-4. PubMed PMID:27441081 PubMed Central PMC4952281.
- Freyermuth, F, Rau, F, Kokunai, Y, Linke, T, Sellier, C, Nakamori, M et al.. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun. 2016;7 :11067. doi: 10.1038/ncomms11067. PubMed PMID:27063795 PubMed Central PMC4831019.
- Dogan, C, De Antonio, M, Hamroun, D, Varet, H, Fabbro, M, Rougier, F et al.. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study. PLoS One. 2016;11 (2):e0148264. doi: 10.1371/journal.pone.0148264. PubMed PMID:26849574 PubMed Central PMC4744025.
- Rau, F, Lainé, J, Ramanoudjame, L, Ferry, A, Arandel, L, Delalande, O et al.. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun. 2015;6 :7205. doi: 10.1038/ncomms8205. PubMed PMID:26018658 PubMed Central PMC4458869.
- Hernández-Hernández, O, Guiraud-Dogan, C, Sicot, G, Huguet, A, Luilier, S, Steidl, E et al.. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. Brain. 2013;136 (Pt 3):957-70. doi: 10.1093/brain/aws367. PubMed PMID:23404338 PubMed Central PMC3580270.
- Huguet, A, Medja, F, Nicole, A, Vignaud, A, Guiraud-Dogan, C, Ferry, A et al.. Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus. PLoS Genet. 2012;8 (11):e1003043. doi: 10.1371/journal.pgen.1003043. PubMed PMID:23209425 PubMed Central PMC3510028.
- Laurent, FX, Sureau, A, Klein, AF, Trouslard, F, Gasnier, E, Furling, D et al.. New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Res. 2012;40 (7):3159-71. doi: 10.1093/nar/gkr1228. PubMed PMID:22156369 PubMed Central PMC3326330.
- Rau, F, Freyermuth, F, Fugier, C, Villemin, JP, Fischer, MC, Jost, B et al.. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011;18 (7):840-5. doi: 10.1038/nsmb.2067. PubMed PMID:21685920 .
- Fugier, C, Klein, AF, Hammer, C, Vassilopoulos, S, Ivarsson, Y, Toussaint, A et al.. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med. 2011;17 (6):720-5. doi: 10.1038/nm.2374. PubMed PMID:21623381 .
- François, V, Klein, AF, Beley, C, Jollet, A, Lemercier, C, Garcia, L et al.. Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs. Nat Struct Mol Biol. 2011;18 (1):85-7. doi: 10.1038/nsmb.1958. PubMed PMID:21186365 .
Foiry L, Dong L, Savouret C, Hubert L, te Riele H, Junien C and Gourdon G. Msh3 is a limiting factor in the formation of intergenerational CTG expansions in transgenic mice. Human Genetics, 2006, 119(5):520-6
Savouret C, Brisson E, Essers J, Kanaar R, Pastink A, te Riele H, Junien C and Gourdon G. CTG repeat instability and size variation timing in repair-deficient mice. The Embo Journal, 2003, 22 :2264-2273.
- Gourdon – Steinert Award 2019, for her work and significant contributions to scientific research on Myotonic Dystrophy. Awarded by the International Myotonic Dystrophy Consortium (IDMC).
- Bassez – Steinert Award 2019, for his work and significant contributions to clinical research on Myotonic Dystrophy. Awarded by the International Myotonic Dystrophy Consortium (IDMC).
- Matloka (PhD student) – Travel Award to attend the Annual Conference of the European Society of Gene Therapy, Barcelona, Spain, 2019. Awarded by European Society of Gene Therapy.
- Klein A. et al, (JCI, 2019) – “Publication of the Month”, November 2019. Awarded by the Oligonucleotide Therapeutics Society (OTS).
Our latest work in the Journal of Cell Biology
Why do neurons exclusively form spherical clathrin-coated pits while muscle cells form extensive flat plaques ? What is the link between “spliceopathies” such as myotonic dystrophy and clathrin?