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
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- Valérie Allamand. Muscle Membrane Serendipity conference : Past, Present, and Future Conference. Médecine/Sciences, 2017, 33, pp.67-67. ⟨10.1051/medsci/201733s116⟩. ⟨hal-03838486⟩
- Valérie Allamand. Génétique : Intérêt du NGS dans un cas atypique de LGMD liée à l’alphadystroglycane. Médecine/Sciences, 2017, 33, pp.57-57. ⟨10.1051/medsci/201733s112⟩. ⟨hal-03838503⟩
- 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-04015397⟩
- Astrid Brull. Gene therapy for LMNA-related congenital muscular dystrophy. LMNA consortium Meeting atInstitute of Health Carlos III – ISCIII, Oct 2017, Madrid, Spain. ⟨hal-03986864⟩
- Rabah Ben Yaou. The French OPALE registry update. LMNA consortium Meeting at Institute of Health Carlos III – ISCIII, Oct 2017, Madrid, Spain. ⟨hal-03986859⟩
- K Piekarowicz, M Beuvin, M Machowska, A Bertrand, Gisèle Bonne, et al.. A muscle hybrid promoter provides specific and effective gene expression after intramuscular and systemic delivery with AAV. European-Society-of-Gene-and-Cell-Therapy (ESCGT) Congress, Oct 2017, Berlin, Germany. Hum. Gene Ther., 28 (12), pp.A44-A45. P096, 2017. ⟨hal-03983944⟩
- Catherine Coirault. Lamin A/C is crucial for skeletal muscle plasticity. 14th IIM (Interuniversity Institute of Myology) meeting, Oct 2017, Assisi, Italy. ⟨hal-03972582⟩
- I. Nelson, M. Beuvin, R. Ben-Yaou, C. Masson, A. Boland, et al.. Novel recessive splice site mutation in POPDC1 ( BVES ) is associated with first-degree atrioventricular block and muscular dystrophy. 22nd International Annual Congress of the World Muscle Society (WMS), Oct 2017, Saint Malo, France. Neuromuscular Disorders, 27, pp.S139-S140, 2017, ⟨10.1016/j.nmd.2017.06.172⟩. ⟨hal-03972940⟩
- C. Macquart, M. Chatzifrangkeskou, M. Gotthardt, Gisèle Bonne, A. Muchir. Abnormal trafficking of connexin 43: A key element in the development of LMNA cardiomyopathy. 22nd International Annual Congress of the World-Muscle-Society (WMS), Oct 2017, Saint Malo, France. Neuromuscular Disorders, 27, pp.S139, 2017, ⟨10.1016/j.nmd.2017.06.171⟩. ⟨hal-03973377⟩
- Mathieu Cerino, Svetlana Gorokhova, P. Laforêt, R. Ben Yaou, Emmanuelle Salort-Campana, et al.. Genetic characterization of a French cohort of GNE -mutation negative inclusion body myopathy patients using exome sequencing. 22nd International Annual Congress of the World-Muscle-Society (WMS), Oct 2017, Saint Malo, France. 27, pp.S149, 2017, ⟨10.1016/j.nmd.2017.06.205⟩. ⟨hal-03973434⟩
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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