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

Noyau-MEC ©Astrid Brull

Equipe BONNE
Gisèle Bonne


Gisèle Bonne


Main publications

  1. Bertrand, AT, Brull, A, Azibani, F, Benarroch, L, Chikhaoui, K, Stewart, CL et al.. Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy. Cells. 2020;9 (4):. doi: 10.3390/cells9040844. PubMed PMID:32244403 PubMed Central PMC7226786.
  2. Harandi, VM, Oliveira, BMS, Allamand, V, Friberg, A, Fontes-Oliveira, CC, Durbeej, M et al.. Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy. Antioxidants (Basel). 2020;9 (3):. doi: 10.3390/antiox9030244. PubMed PMID:32197453 PubMed Central PMC7139799.
  3. Benarroch, L, Bonne, G, Rivier, F, Hamroun, D. The 2020 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2019;29 (12):980-1018. doi: 10.1016/j.nmd.2019.10.010. PubMed PMID:31791870 .
  4. Piekarowicz, K, Bertrand, AT, Azibani, F, Beuvin, M, Julien, L, Machowska, M et al.. A Muscle Hybrid Promoter as a Novel Tool for Gene Therapy. Mol Ther Methods Clin Dev. 2019;15 :157-169. doi: 10.1016/j.omtm.2019.09.001. PubMed PMID:31660418 PubMed Central PMC6807297.
  5. Wahbi, K, Ben Yaou, R, Gandjbakhch, E, Anselme, F, Gossios, T, Lakdawala, NK et al.. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies. Circulation. 2019;140 (4):293-302. doi: 10.1161/CIRCULATIONAHA.118.039410. PubMed PMID:31155932 .
  6. De Ridder, W, Nelson, I, Asselbergh, B, De Paepe, B, Beuvin, M, Ben Yaou, R et al.. Muscular dystrophy with arrhythmia caused by loss-of-function mutations in BVES. Neurol Genet. 2019;5 (2):e321. doi: 10.1212/NXG.0000000000000321. PubMed PMID:31119192 PubMed Central PMC6501641.
  7. Thompson, R, Bonne, G, Missier, P, Lochmüller, H. Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome. Emerg Top Life Sci. 2019;3 (1):19-37. doi: 10.1042/ETLS20180100. PubMed PMID:30931400 PubMed Central PMC6436731.
  8. Bolduc, V, Foley, AR, Solomon-Degefa, H, Sarathy, A, Donkervoort, S, Hu, Y et al.. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. JCI Insight. 2019;4 (6):. doi: 10.1172/jci.insight.124403. PubMed PMID:30895940 PubMed Central PMC6483063.
  9. Rodriguez, BM, Khouzami, L, Decostre, V, Varnous, S, Pekovic-Vaughan, V, Hutchison, CJ et al.. N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene. Hum Mol Genet. 2018;27 (19):3353-3360. doi: 10.1093/hmg/ddy243. PubMed PMID:29982513 .
  10. Azibani, F, Brull, A, Arandel, L, Beuvin, M, Nelson, I, Jollet, A et al.. Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy. Mol Ther Nucleic Acids. 2018;10 :376-386. doi: 10.1016/j.omtn.2017.12.012. PubMed PMID:29499949 PubMed Central PMC5862133.

AFM Telethon : innover pour guérir
Agence nationale de la recherche
Congenital Muscular Dystrophy Research
Muscular Dystrophy UK - Fighting Muscle-wasting conditions
Solving the Unsolved Rare Diseases
European Research Area Network on Cardiovascular Diseases

Our last work on the OJRD

A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome

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