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 |
|---|
- Gisèle Bonne. 2002 - 2023 : l’Odyssée de… la Myologie. 20èmes Journées de la Société Française de Myologie, Societe Française de Myologie, Nov 2023, La Baule (France), France. ⟨hal-04319081⟩
- V. Decostre, C. Chikhaoui, C. Vigouroux, A. Behin, G. Bassez, et al.. VP429 Impaired skeletal muscle strength in adult patients with laminopathies. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S159-S160, ⟨10.1016/j.nmd.2023.07.370⟩. ⟨hal-04280272⟩
- L. Benarroch, I. Nelson, T. Stojkovic, B Mohand Oumoussa, H. Madry, et al.. P166 Deciphering the genetic cause of oculopharyngodistal myopathy in a French cohort using Cas9-targeted long-read sequencing. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S141, ⟨10.1016/j.nmd.2023.07.298⟩. ⟨hal-04280249⟩
- J. de Winter, L. van de Vondel, Gisèle Bonne, T. Stojkovic, S. Elouej, et al.. P158 Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S139, ⟨10.1016/j.nmd.2023.07.290⟩. ⟨hal-04280233⟩
- M Gomez Garcia, R. Garcia-Uzquiano, L. Le Goff, V. Manel, I. Dabaj, et al.. P431 Steroid treatment may change natural history in congenital laminopathies. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S160, ⟨10.1016/j.nmd.2023.07.372⟩. ⟨hal-04280227⟩
- L. Benarroch, J. Madsen-Østerbye, M. Abdelhalim, K. Mamchaoui, J. Ohana, et al.. A robust and practical myogenic system to explore cellular and genomic features of muscle differentiation. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston, United States. pp.S158, ⟨10.1016/j.nmd.2023.07.363⟩. ⟨hal-04280205⟩
- A. Atalaia, R. Thompson, L. Matalonga, C. Hernandez-Ferrer, A. Corvo, et al.. P192 The open-access treatabolome platform enhances the visibility of treatable and actionable genes in RD-connect's GPAP and other clinical diagnosis support tools. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston, United States. pp.S142, ⟨10.1016/j.nmd.2023.07.301⟩. ⟨hal-04280259⟩
- A. Merlet, E. Lacène, I. Nelson, G. Brochier, C. Labasse, et al.. P338 Clinical, morphological, and proteomic features of patients suspected of X-linked myopathy with excessive autophagy (XMEA). 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S99, ⟨10.1016/j.nmd.2023.07.136⟩. ⟨hal-04280238⟩
- M. Okubo, A. Brull, M. Beuvin, N. Mougenot, V. Paradis, et al.. O03 In vivo gene therapy for striated muscle laminopathy. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S67, ⟨10.1016/j.nmd.2023.07.018⟩. ⟨hal-04280254⟩
- Gisèle Bonne, Martin Krahn. Concept de gènes actionnables et application dans le domaine neuromusculaire.. 25èmes Journées Neuromusculaires de Marseille, Sep 2023, Marseille, France. ⟨hal-04189737⟩
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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