Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function (Articolo in rivista)

Type
Label
  • Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function (Articolo in rivista) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Alternative label
  • Caroline Huze´,1 Stephanie Bauche´,2,3,4 Pascale Richard,5 Frederic Chevessier,2,6 Evelyne Goillot,1 Karen Gaudon,5 Asma Ben Ammar,2,3,7 Annie Chaboud,8 Isabelle Grosjean,8 Heba-Aude Lecuyer,1 Veronique Bernard,9 Andree Rouche,2 Nektaria Alexandri,2 Thierry Kuntzer,10 Michel Fardeau,11 Emmanuel Fournier,12 Andrea Brancaccio,13 Markus A. Ruegg,14 Jeanine Koenig,2,3,15 Bruno Eymard,2,3,11 Laurent Schaeffer,1 and Daniel Hantai2,3,11 (2009)
    Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function
    in American journal of human genetics
    (literal)
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  • Caroline Huze´,1 Stephanie Bauche´,2,3,4 Pascale Richard,5 Frederic Chevessier,2,6 Evelyne Goillot,1 Karen Gaudon,5 Asma Ben Ammar,2,3,7 Annie Chaboud,8 Isabelle Grosjean,8 Heba-Aude Lecuyer,1 Veronique Bernard,9 Andree Rouche,2 Nektaria Alexandri,2 Thierry Kuntzer,10 Michel Fardeau,11 Emmanuel Fournier,12 Andrea Brancaccio,13 Markus A. Ruegg,14 Jeanine Koenig,2,3,15 Bruno Eymard,2,3,11 Laurent Schaeffer,1 and Daniel Hantai2,3,11 (literal)
Pagina inizio
  • 155 (literal)
Pagina fine
  • 167 (literal)
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  • 85 (literal)
Rivista
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  • Scopu (literal)
  • ISI Web of Science (WOS) (literal)
  • PubMe (literal)
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  • 1Equipe Diffe´renciation Neuromusculaire, UMR 5239, E´ cole Normale Supe´rieure Lyon, CNRS, Universite´ Lyon 1, Lyon, France; 2INSERM, UMR S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle, Ho^pital Pitie´-Salpe^trie`re, Paris, France; 3Universite´ Pierre et Marie Curie, Paris, France; 4E´ cole Pratique des Hautes Etudes, Paris, France; 5Assistance Publique-Ho^pitaux de Paris, Unite´ Fonctionnelle Cardioge´ne´tique et Myoge´ne´tique, Ho^pital Pitie´-Salpe ^trie`re, Paris, France; 6Max-Planck-Institut fu¨r Medizinische Forschung, Heidelberg, Germany; 7Institut National de Neurologie, Universite´ Tunis El Manar, Tunis, Tunisia; 8Plateau d'analyse des prote´ines, Institut Fe´de´ratif de Recherche 128, Lyon, France; 9Inserm, U686, Universite´ Paris-Descartes, Paris, France; 10Nerve-muscle unit, neurology service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 11Assistance Publique- Ho^pitaux de Paris, Centre national de re´fe´rence des maladies neuromusculaires Paris-Est, Institut de Myologie, Ho^pital Pitie´-Salpe^trie`re, Paris, France; 12Assistance Publique-Ho^pitaux de Paris, Service d'e´lectrophysiologie, Ho^pital Pitie´-Salpe^trie`re, Paris, France; 13Istituto di Chimica del Riconoscimento Molecolare, Universita` Cattolica del Sacro Cuore, Rome, Italy; 14Biozentrum, Universita¨t Basel, Basel, Switzerland; 15Universite´ Victor Segalen Bordeaux 2, Bordeaux, France (literal)
Titolo
  • Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function (literal)
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 wildtype 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. (literal)
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