Frédéric Chevessier

Publications of Frédéric Chevessier

• A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR εL221F mutation.

  Authors: Frédéric Chevessier, Christoph Peter, Ulrike Mersdorf, Emmanuelle Girard, Eric Krejci, Joseph J McArdle, Veit Witzemann

  Neurobiology of disease. 12/2011; 45(3):851-61.

  We have generated a new mouse model for congenital myasthenic syndromes by inserting the missense mutation L221F into the ε subunit of the acetylcholine receptor by homologous recombination. ThisWe have generated a new mouse model for congenital myasthenic syndromes by inserting the missense mutation L221F into the ε subunit of the acetylcholine receptor by homologous recombination. This mutation has been identified in man to cause a mild form of slow-channel congenital myasthenic syndrome with variable penetrance. In our mouse model we observe as in human patients prolonged endplate currents. The summation of endplate potentials may account for a depolarization block at increasing stimulus frequencies, moderate reduced muscle strength and tetanic fade. Calcium and intracellular vesicle accumulation as well as junctional fold loss and organelle degeneration underlying a typical endplate myopathy, were identified. Moreover, a remodeling of neuromuscular junctions occurs in a muscle-dependent pattern expressing variable phenotypic effects. Altogether, this mouse model provides new insight into the pathophysiology of congenital myasthenia and serves as a new tool for deciphering signaling pathways induced by excitotoxicity at peripheral synapses.

• Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function.

  Authors: Caroline Huzé, Stéphanie Bauché, Pascale Richard, Frédéric Chevessier, Evelyne Goillot, Karen Gaudon, Asma Ben Ammar, Annie Chaboud, Isabelle Grosjean, Heba-Aude Lecuyer [......] Nektaria Alexandri, Thierry Kuntzer, Michel Fardeau, Emmanuel Fournier, Andrea Brancaccio, Markus A Rüegg, Jeanine Koenig, Bruno Eymard, Laurent Schaeffer, Daniel Hantaï

  American journal of human genetics. 07/2009;

  We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of theWe report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.

  Download

• A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions.

  Authors: Frédéric Chevessier, Emmanuelle Girard, Jordi Molgó, Bartling Sönke, Jeanine Koenig, Daniel Hantaï, Veit Witzemann

  Human molecular genetics. 09/2008;

  In the muscle-specific tyrosine kinase receptor gene MUSK a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome. We generated oneIn the muscle-specific tyrosine kinase receptor gene MUSK a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome. We generated one mouse line carrying the homozygous missense mutation V789M in musk (musk(V789M/V789M) mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (musk(V789M/-)mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function, and viability. In contrast, adult musk(V789M/-) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions, and hunchback. Musk(V789M/-) diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a congenital myasthenic syndrome. The diaphragm of adult musk(V789M/-) mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk(V789M/-) mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation, and maintenance as well as for studying the pathophysiology of a congenital myasthenic syndrome due to MuSK mutations.

• The origin of tubular aggregates in human myopathies.

  Authors: Frédéric Chevessier, Stéphanie Bauché-Godard, Jean-Paul Leroy, Jeanine Koenig, Marion Paturneau-Jouas, Bruno Eymard, Daniel Hantaï, Martine Verdière-Sahuqué

  The Journal of pathology. 12/2005; 207(3):313-23.

  Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation andTubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the present study reports the electron microscopic analysis and protein characterization of tubular aggregates in six patients with 'tubular aggregate myopathy'. Three of the six patients also presented with myasthenic features. A large panel of immunochemical markers located in the sarcoplasmic reticulum, T-tubules, mitochondria, and nucleus was used. Despite differences in clinical phenotype, the composition of tubular aggregates, which contained proteins normally segregated differently along the sarcoplasmic reticulum architecture, was similar in all patients. All of these proteins, calsequestrin, RyR, triadin, SERCAs, and sarcalumenin, are involved in calcium uptake, storage, and release. The dihydropyridine receptor, DHPR, specifically located in the T-tubule, was also present in tubular aggregates in all patients. COX-2 and COX-7 mitochondrial proteins were not found in tubular aggregates, despite being observed close to them in the muscle fibre. The nuclear membrane protein emerin was found in only one case. Electron microscopy revealed vesicular budding from nuclei, and the presence of SAR-1 GTPase protein in tubular aggregates shown by immunochemistry, in all patients, suggests that tubular aggregates could arise from endoplasmic reticulum exit sites. Taken together, these results cast new light on the composition and significance of tubular aggregates.

• [Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene]

  Authors: Frédéric Chevessier, Brice Faraut, Aymeric Ravel-Chapuis, Pascale Richard, Karen Gaudon, Stéphanie Bauché, Cassandra Prioleau, Ruth Herbst, Evelyne Goillot, Christine Ioos [......] Shahram Attarian, Jean-Paul Leroy, Emmanuel Fournier, Claire Legay, Laurent Schaeffer, Jeanine Koenig, Michel Fardeau, Bruno Eymard, Jean Pouget, Daniel Hantaï

  Journal de la Société de biologie. 02/2005; 199(1):61-77.

  Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous atCongenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

• MUSK, a new target for mutations causing congenital myasthenic syndrome.

  Authors: Frédéric Chevessier, Brice Faraut, Aymeric Ravel-Chapuis, Pascale Richard, Karen Gaudon, Stéphanie Bauché, Cassandra Prioleau, Ruth Herbst, Evelyne Goillot, Christine Ioos [......] Shahram Attarian, Jean-Paul Leroy, Emmanuel Fournier, Claire Legay, Laurent Schaeffer, Jeanine Koenig, Michel Fardeau, Bruno Eymard, Jean Pouget, Daniel Hantaï

  Human molecular genetics. 01/2005; 13(24):3229-40.

  We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified twoWe report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

• A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions

  Authors: Frédéric Chevessier, Emmanuelle Girard, Jordi Molgó, Sönke Bartling, Jeanine Koenig, Daniel Hantaï, Veit Witzemann

  In the muscle-specific tyrosine kinase receptor gene MUSK , a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). WeIn the muscle-specific tyrosine kinase receptor gene MUSK , a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk ( musk V789M/V789M mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain ( musk V789M/− mice). We report here that musk V789M/V789M mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk V789M/− mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk V789M/− diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult musk V789M/− mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk V789M/− mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations.

• A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions

  Authors: Frédéric Chevessier, E Girard, J Molgó, S. Bartling, J Koenig, D Hantai, Veit Witzemann

  Hum. Mol. Gen., v.17, 3577-3595 (2008).

  In the muscle−specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). WeIn the muscle−specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk (musk(V789M/V789M) mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (musk(V789M/−) mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk(V789M/−) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk(V789M/−) diaphragm develops less force upon direct or nerve−induced stimulation. A profound tetanic fade is observed following nerve−evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult musk(V789M/−) mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk(V789M/−) mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations.