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 |
|---|
- France Nelson, France Stojkovic, France Allamand, France Leturcq, Henri-Marc Becane, et al.. Laminin α2 Deficiency-Related Muscular Dystrophy Mimicking Emery-Dreifuss and Collagen VI related Diseases. Journal of Neuromuscular Diseases, 2015, 2 (3), pp.229 - 240. ⟨10.3233/JND-150093⟩. ⟨hal-01681760⟩
- Juliette Nectoux, Rafael de Cid, Sylvain Baulande, France Leturcq, Jon Andoni Urtizberea, et al.. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing. European Journal of Human Genetics, 2015, 23 (7), pp.929-934. ⟨10.1038/ejhg.2014.223⟩. ⟨hal-02190709⟩
- Aurélie Nicolas, Céline Raguénès-Nicol, Rabah Ben Yaou, Sarah Ameziane-Le Hir, Angélique Chéron, et al.. Becker muscular dystrophy severity is linked to the structure of dystrophin.. Human Molecular Genetics, 2015, 24 (5), pp.1267-79. ⟨10.1093/hmg/ddu537⟩. ⟨hal-01117005⟩
- Florian Barthelemy, Claire L. Navarro, Racha Fayek, Nathalie da Silva, Patrice Roll, et al.. Truncated prelamin A expression in HGPS-like patients: a transcriptional study. European Journal of Human Genetics, 2015, 23 (8), pp.1051 - 1061. ⟨10.1038/ejhg.2014.239⟩. ⟨hal-01597886⟩
- Frédérique Rau, Jeanne Lainé, Laetitita Ramanoudjame, Arnaud Ferry, Ludovic Arandel, et al.. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nature Communications, 2015, 6 (1), pp.7205. ⟨10.1038/ncomms8205⟩. ⟨hal-01162385⟩
- Annachiara de Sandre-Giovannoli, Nicolas Lévy, Rabah Ben Yaou, France Leturcq, Giovanna Lattanzi, et al.. An overview of new translational, clinical and therapeutic perspectives in laminopathies and other nuclear envelope-related diseases.. Orphanet Journal of Rare Diseases, 2015, 10 (Suppl 2), ⟨10.1186/1750-1172-10-S2-I1⟩. ⟨hal-01769449⟩
- Laetitia Ramanoudjame, Claire Rocancourt, Jeanne Lainé, Arnaud Klein, Lucette Joassard, et al.. Two novel COLVI long chains in zebrafish that are essential for muscle development. Human Molecular Genetics, 2015, 24 (23), pp.6624-6639. ⟨10.1093/hmg/ddv368⟩. ⟨hal-01594462⟩
- Gisèle Bonne, Rabah Ben Yaou. A common French-Italian laminopathy registry – update & future prospects. Orphanet Journal of Rare Diseases, 2015, 10 (Suppl 2), pp.O31. ⟨10.1186/1750-1172-10-S2-O31⟩. ⟨hal-01227847⟩
- Imen Dorboz, Marie Coutelier, Anne T. Bertrand, Jean-Hubert Caberg, Monique Elmaleh-Bergès, et al.. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1. Orphanet Journal of Rare Diseases, 2014, 9 (1), pp.174. ⟨10.1186/s13023-014-0174-9⟩. ⟨hal-01110718⟩
- Caroline Le Guiner, Marie Montus, Laurent Servais, Yan Cherel, Virginie François, et al.. Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients. Molecular Therapy, 2014, 22 (11), pp.1923-1935. ⟨10.1038/mt.2014.151⟩. ⟨inserm-02447482⟩
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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