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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- Christine Schwartz, Martina Fischer, Kamel Mamchaoui, Anne Bigot, Thevy Lok, et al.. Lamins and nesprin-1 mediate inside-out mechanical coupling in muscle cell precursors through FHOD1. Scientific Reports, 2017, 7 (1), pp.1253. ⟨10.1038/s41598-017-01324-z⟩. ⟨hal-01518113⟩
- Gisèle Bonne. Insights in the pathophysiology of striated muscle Laminopathies. 2nd International Meeting on Laminopathies, Giovanna Lattanzi, Apr 2017, Bologna, Italy. ⟨hal-03972901⟩
- Margot Saunier, Corine Gartioux, Maud Beuvin, Nathalie Mougenot, Gisèle Bonne, et al.. Collagen VI deficiency: the heart of the matter. Printemps de la Cardiologie, Apr 2017, Nantes, France. ⟨hal-03996993⟩
- Gisèle Bonne. Insights in the pathophysiology of striated muscle Laminopathies. Workshop of COST Action CA15214 An Integrative Action for Multidisciplinary Studies on Cellular Structural Networks, Pavel Hodzak, Mar 2017, Prague, Czech Republic. ⟨hal-03972189⟩
- Mark Pines, Oshrat Levi, Olga Genin, Adi Lavy, Corrado Angelini, et al.. Elevated Expression of Moesin in Muscular Dystrophies. American Journal of Pathology, 2017, 187 (3), pp.654-664. ⟨10.1016/j.ajpath.2016.11.013⟩. ⟨hal-03838202⟩
- Simon Guiraud, Tiffany Migeon, Arnaud Ferry, Zhiyong Chen, Souhila Ouchelouche, et al.. HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect. American Journal of Pathology, 2017, 187 (3), pp.505-516. ⟨10.1016/j.ajpath.2016.10.020⟩. ⟨hal-03831011⟩
- Mathieu Cerino, Svetlana Gorokhova, Pascal Laforet, Rabah Ben Yaou, Emmanuelle Salort-Campana, et al.. Genetic Characterization of a French Cohort of GNE-mutation negative inclusion body myopathy patients with exome sequencing. Muscle & Nerve, 2017, 56, pp.993-997. ⟨10.1002/mus.25638⟩. ⟨hal-01741741⟩
- Audrey de Jong, Serge Carreira, Na Na, Aude Carillion, Cheng Jiang, et al.. Diaphragmatic function is enhanced in fatty and diabetic fatty rats. PLoS ONE, 2017, 12 (3), pp.e0174043. ⟨10.1371/journal.pone.0174043⟩. ⟨hal-01502168⟩
- Stéphanie Bauché, Geoffroy Vellieux, Damien Sternberg, Marie-Joséphine Fontenille, Elodie de Bruyckere, et al.. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. Journal of Neurology, 2017, 264 (8), pp.1791-1803. ⟨10.1007/s00415-017-8569-x⟩. ⟨hal-01653176⟩
- Gisèle Bonne, Francois Rivier, Dalil Hamroun. The 2018 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscular Disorders, 2017, 27 (12), pp.1152-1183. ⟨10.1016/j.nmd.2017.10.005⟩. ⟨hal-01668854⟩
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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