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Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function |
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| Authors: | Caroline Huzé Pascale Richard Evelyne Goillot Asma Ben Ammar Annie Chaboud Heba-Aude Lecuyer Andrée Rouche Thierry Kuntzer Emmanuel Fournier Markus A Rüegg Bruno Eymard Laurent Schaeffer |
| Institution: | 1 Equipe Différenciation Neuromusculaire, UMR 5239, École Normale Supérieure Lyon, CNRS, Université Lyon 1, Lyon, France 2 INSERM, UMR S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle, Hôpital Pitié-Salpêtrière, Paris, France 3 Université Pierre et Marie Curie, Paris, France 4 École Pratique des Hautes Etudes, Paris, France 5 Assistance Publique-Hôpitaux de Paris, Unité Fonctionnelle Cardiogénétique et Myogénétique, Hôpital Pitié-Salpêtrière, Paris, France 6 Max-Planck-Institut für Medizinische Forschung, Heidelberg, Germany 7 Institut National de Neurologie, Université Tunis El Manar, Tunis, Tunisia 8 Plateau d'analyse des protéines, Institut Fédératif de Recherche 128, Lyon, France 9 Inserm, U686, Université Paris-Descartes, Paris, France 10 Nerve-muscle unit, neurology service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland 11 Assistance Publique-Hôpitaux de Paris, Centre national de référence des maladies neuromusculaires Paris-Est, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France 12 Assistance Publique-Hôpitaux de Paris, Service d'électrophysiologie, Hôpital Pitié-Salpêtrière, Paris, France 13 Istituto di Chimica del Riconoscimento Molecolare, Università Cattolica del Sacro Cuore, Rome, Italy 14 Biozentrum, Universität Basel, Basel, Switzerland 15 Université Victor Segalen Bordeaux 2, Bordeaux, France |
| Abstract: | 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 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 α-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. |
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