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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- V. Sardone, J. Domingos, S. Torelli, A. Jones, M. Ellis, et al.. Dystrophin quantification in Duchenne and Becker muscular dystrophy: correlation between dystrophin protein and clinical phenotype. 11th UK Neuromuscular Translational Research Conference, Apr 2018, Cambridge, United Kingdom. Neuromuscular Disorders, 28, pp.S7-S8, 2018, ⟨10.1016/S0960-8966(18)30310-9⟩. ⟨hal-03973445⟩
- Alexandre Janin, Delphine Bauer, Francesca Ratti, Camille Valla, Anne T Bertrand, et al.. SMAD6 overexpression leads to accelerated myogenic differentiation of LMNA mutated cells. Scientific Reports, 2018, 8 (1), ⟨10.1038/s41598-018-23918-x⟩. ⟨hal-03270318⟩
- Feriel Azibani, Astrid Brull, Ludovic Arandel, Maud Beuvin, Isabelle Nelson, et al.. Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy. Molecular Therapy - Nucleic Acids, 2018, 10, pp.376 - 386. ⟨10.1016/j.omtn.2017.12.012⟩. ⟨hal-03269960⟩
- Gabriella Captur, Eloisa Arbustini, Gisèle Bonne, Petros Syrris, Kevin Mills, et al.. Lamin and the heart. Heart, 2018, 104 (6), pp.468-479. ⟨10.1136/heartjnl-2017-312338⟩. ⟨hal-03285171⟩
- Isabelle Nelson, Maud Beuvin, Rabah Ben-Yaou, Cecile Masson, Anne Boland, et al.. Nouvelle mutation d’épissage du gène POPDC1 (BVES) associée à des blocs de conduction cardiaque du 1er degré et une dystrophie musculaire. 9èmes Assises de génétique humaine et médicale, Jan 2018, Nantes, France. . ⟨hal-03986833⟩
- Jocelyn Laporte, Raphael Schneider, Edoardo Malfatti, Gisèle Bonne, France Leturcq, et al.. Analyse intégrée du grand projet de séquençage MYOCAPTURE d’identification de nouveaux gènes de myopathies. 9èmes Assises de Génétique Humaine et Médicale, Jan 2018, Nantes, France. ⟨hal-03986850⟩
- Abdallah Fayssoil, Rabah Ben Yaou, Adam Ogna, Cendrine Chaffaut, France Leturcq, et al.. Left bundle branch block in Duchenne muscular dystrophy: Prevalence, genetic relationship and prognosis. PLoS ONE, 2018, 13 (1), pp.e0190518. ⟨10.1371/journal.pone.0190518⟩. ⟨hal-04015387⟩
- Nicolas Vignier, Maria Chatzifrangkeskou, Blanca Morales Rodriguez, Mathias Mericskay, Nathalie Mougenot, et al.. Rescue of biosynthesis of nicotinamide adenine dinucleotide protects the heart in cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics, 2018, 27 (22), pp.3870-3880. ⟨10.1093/hmg/ddy278⟩. ⟨hal-01958003⟩
- Zoi Galata, Ismini Kloukina, Ioanna Kostavasili, Aimilia Varela, Constantinos H Davos, et al.. Amelioration of desmin network defects by αB-crystallin overexpression confers cardioprotection in a mouse model of dilated cardiomyopathy caused by LMNA gene mutation. Journal of Molecular and Cellular Cardiology, 2018, 125, pp.73-86. ⟨10.1016/j.yjmcc.2018.10.017⟩. ⟨hal-02292777⟩
- Blanca Morales Rodriguez, Lara Khouzami, Valérie Decostre, Shaida Varnous, Vanja Pekovic-Vaughan, et al.. N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene. Human Molecular Genetics, 2018, 27 (19), pp.3353-3360. ⟨10.1093/hmg/ddy243⟩. ⟨hal-01961216⟩
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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