Genetics and pathophysiology of neuromuscular disorders linked to the extracellular matrix and to the nucleus
Genetics and pathophysiology of neuromuscular disorders linked to the extracellular matrix and to the nucleus
Our research interests focus on two groups of neuromuscular disorders (NMD): myopathies due to abnormalities of the myomatrix and of the nucleus. The long-term objective of our work is to propose relevant therapeutic options based on our knowledge of the genetic basis and of the underlying pathomechanisms at play in these rare diseases.
Research Project: Genetics and pathophysiology of neuromuscular disorders linked to the extracellular matrix and to the nucleus
Our team focuses on 2 groups of neuromuscular disorders: myopathies due to the defective myomatrix (collagen VI and other components of the extracellular matrix) and to defects of the myonucleus (Emery-Dreifuss muscular dystrophy and other striated muscle laminopathies due to mutations in the laminA/C gene or genes encoding components of nuclear membrane). These myopathies share some clinical features, notably prominent contractures, and constitute differential diagnosis[in1] .
These disorders are highly heterogeneous, clinically and genetically, and to date no treatment is available. Our previous work led us to identify the involvement of various genetic alterations and to develop tools (cellular and animal models) that are crucial for deciphering pathomechanisms, understanding the molecular defects and unveiling therapeutic targets.
We are still facing several challenges and bottlenecks: 1) a number of patients are still awaiting molecular diagnosis; 2) relevant biomarkers are scarce; 3) functions of the involved proteins and underlying pathomechanisms are still poorly understood … We previously have and continue to tackle several transverse processes (e.g. contractile dysfunction, defective mechanosensing, fibrosis …) using our specific expertise (nuclear envelop, nucleoplasm, extracellular matrix…).
Current research axes:
- Definition of genetic and clinical spectrum and delineation of natural history of these NMDs,
- Development of new tools to validate genetic variants identified through NGS (next generation sequencing),
- Deciphering pathomechanisms that affect skeletal and/or cardiac muscle, with the overall goal of identifying and assessing therapeutic options for these disorders.
Our work is carried out on biological material derived from patients (DNA, RNA cultured cells, or muscle biopsies), and on animal models developed in the team (mouse, zebrafish).
Noyau-MEC ©Astrid Brull
| Name | Position | ORCID |
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- Pia Bernasconi, Nicola Carboni, Giulia Ricci, Gabriele Siciliano, Luisa Politano, et al.. Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes. Nucleus, 2018, 9 (1), pp.337-349. ⟨10.1080/19491034.2018.1467722⟩. ⟨hal-02297778⟩
- Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, et al.. Allele‐specific silencing therapy for Dynamin 2‐related dominant centronuclear myopathy. EMBO Molecular Medicine, 2018, 10 (2), pp.239-253. ⟨10.15252/emmm.201707988⟩. ⟨hal-02000303⟩
- Aurélien Perrin, Philippe Latour, Vincent Procaccio, Claude Jardel, Mathieu Cerino, et al.. Vers une harmonisation du diagnostic par séquençage haut débit des maladies neuromusculaires : Actions de la sous-commission Génétique Moléculaire de Filnemus. Médecine/Sciences, 2018, 34 (Hors-série 2), pp.20-22. ⟨10.1051/medsci/201834s206⟩. ⟨hal-01938567⟩
- Marine Guilbaud, Christel Gentil, Cecile Peccate, Elena Gargaun, Isabelle Holtzmann, et al.. miR-708-5p and miR-34c-5p are involved in nNOS regulation in dystrophic context. Skeletal Muscle, 2018, 8 (1), pp.15. ⟨10.1186/s13395-018-0161-2⟩. ⟨hal-01792009⟩
- Coline Macquart, Rene Jüttner, Blanca Morales Rodriguez, Caroline Le Dour, Florence Lefebvre, et al.. Microtubule cytoskeleton regulates Connexin 43 localization and cardiac conduction in cardiomyopathy caused by mutation in A-type lamins gene. Human Molecular Genetics, 2018, 28 (24), pp.4043-4052. ⟨10.1093/hmg/ddy227⟩. ⟨hal-02505679⟩
- Candice Kutchukian, Peter Szentesi, Bruno Allard, Delphine Trochet, Maud Beuvin, et al.. Impaired excitation-contraction coupling in muscle fibres from the dynamin2 R465W mouse model of centronuclear myopathy. The Journal of Physiology, 2017, 595 (24), pp.7369-7382. ⟨10.1113/JP274990⟩. ⟨hal-03819840⟩
- Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, et al.. Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy. Circulation. Arrhythmia and electrophysiology, 2017, 10 (12), pp.428-431. ⟨10.15252/emmm.201707988⟩. ⟨hal-04001377⟩
- Céline Tard, Vincent Tiffreau, Emmanuelle Jaillette, Fabienne Jouen, Isabelle Nelson, et al.. Anti-HMGCR antibody–related necrotizing zutoimmune myopathy mimicking muscular dystrophy. Neuropediatrics, 2017, 48 (06), pp.473-476. ⟨10.1055/s-0037-1604402⟩. ⟨hal-03855669⟩
- Valérie Allamand, Isabelle Nelson, Maud Beuvin, Corine Gartioux, Fanny Roth, et al.. A new gene for myopathies with prominent contractures?: The importance of validation.... Journée Filnemus 2017, Nov 2017, Paris, France. ⟨hal-04029252⟩
- Abdallah Fayssoil, Rabah Ben Yaou, Adam Ogna, France Leturcq, Olivier Nardi, et al.. Clinical profiles and prognosis of acute heart failure in adult patients with dystrophinopathies on home mechanical ventilation. ESC Heart Failure, 2017, 4 (4), pp.527-534. ⟨10.1002/ehf2.12165⟩. ⟨hal-04015409⟩
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Our last work on the OJRD
A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome