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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- Rabah Ben Yaou, Aurelie Hubert, Isabelle Nelson, Julia R. Dahlqvist, David Gaist, et al.. Clinical heterogeneity and phenotype/genotype findings in 5 families with &ITGYG1&IT deficiency. Neurology Genetics, 2017, 3 (6), pp.e208. ⟨10.1212/NXG.0000000000000208⟩. ⟨hal-04010378v2⟩
- D. Avila-Smirnow, L. Gueneau, S. Batonnet-Pichon, F. Delort, H.-M. Bécane, et al.. Cardiac arrhythmia and late-onset muscle weakness caused by a myofibrillar myopathy with unusual histopathological features due to a novel missense mutation in FLNC. Revue Neurologique, 2016, 172 (10), pp.594-606. ⟨10.1016/j.neurol.2016.07.017⟩. ⟨hal-04021574⟩
- L. Davignon, C. Chauveau, C. Julien, C. Dill, L. Duband-Goulet, et al.. Loss-of-function mutation of TRIP4 causes a novel form of congenital muscle disease and reveals the transcription coactivator ASC-1 as a new regulator of skeletal myogenesis. Neuromuscular Disorders, 2016, 26 (suppl 2), pp.S118--S119. ⟨10.1016/j.nmd.2016.06.121⟩. ⟨hal-01415936⟩
- Stéphanie Bauché, Seana O’regan, Yoshiteru Azuma, Fanny Laffargue, Grace Mcmacken, et al.. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. American Journal of Human Genetics, 2016, 99 (3), pp.753 - 761. ⟨10.1016/j.ajhg.2016.06.033⟩. ⟨hal-01680226⟩
- Isabelle Marey, Rabah Ben Yaou, Nathalie Deburgrave, Aurélie Vasson, Juliette Nectoux, et al.. Non Random Distribution of DMD Deletion Breakpoints and Implication of Double Strand Breaks Repair and Replication Error Repair Mechanisms. Journal of Neuromuscular Diseases, 2016, 3 (2), pp.227 - 245. ⟨10.3233/JND-150134⟩. ⟨hal-01815023⟩
- Laurianne Davignon, Claire Chauveau, Cédric Julien, Corinne Dill, Isabelle Duband-Goulet, et al.. The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease. Human Molecular Genetics, 2016, 25 (8), pp.1559--1573. ⟨10.1093/hmg/ddw033⟩. ⟨hal-01295646⟩
- M. Saunier, C.G. Bönnemann, M. Durbeej, V. Allamand. 212th ENMC International Workshop: Animal models of congenital muscular dystrophies, May 29th-31st, 2015 in Naarden, The Netherlands,. Neuromuscular Disorders, 2016, 26 (3), pp.252-259. ⟨10.1016/j.nmd.2016.02.002⟩. ⟨hal-01293003⟩
- Marie-Elodie Cattin, Arnaud Ferry, Alban Vignaud, Nathalie Mougenot, Adeline Jacquet, et al.. Mutation in lamin A/C sensitizes the myocardium to exercise-induced mechanical stress but has no effect on skeletal muscles in mouse. Neuromuscular Disorders, 2016, ⟨10.1016/j.nmd.2016.05.010⟩. ⟨hal-01329664⟩
- Elena Gargaun, Andreea Mihaela Seferian, Ruxandra Cardas, Anne-Gaelle Le Moing, Catherine Delanoe, et al.. EGR2 mutation enhances phenotype spectrum of Dejerine-Sottas syndrome. Journal of Neurology, 2016, 263 (7), pp.1456-1458. ⟨10.1007/s00415-016-8153-9⟩. ⟨hal-03604457⟩
- Rafael de Cid, Rabah Ben Yaou, Carinne Roudaut, Karine Charton, Sylvain Baulande, et al.. A new titinopathy. Neurology, 2015, 85 (24), pp.2126-2135. ⟨10.1212/WNL.0000000000002200⟩. ⟨hal-02336883⟩
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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