Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.

Détails

Ressource 1Télécharger: BIB_7B8117A7C642.P001.pdf (1860.59 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_7B8117A7C642
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Etude de cas (case report): rapporte une observation et la commente brièvement.
Collection
Publications
Titre
Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.
Périodique
American Journal of Human Genetics
Auteur(s)
Huzé C., Bauché S., Richard P., Chevessier F., Goillot E., Gaudon K., Ben Ammar A., Chaboud A., Grosjean I., Lecuyer H.A., Bernard V., Rouche A., Alexandri N., Kuntzer T., Fardeau M., Fournier E., Brancaccio A., Rüegg M.A., Koenig J., Eymard B., Schaeffer L., Hantaï D.
ISSN
1537-6605[electronic]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
85
Numéro
2
Pages
155-167
Langue
anglais
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
Résumé
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 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.
Mots-clé
Adult, Agrin/chemistry, Agrin/genetics, Animals, Biopsy, Cell Line, DNA Mutational Analysis, Dystroglycans/metabolism, Female, Humans, Male, Models, Chemical, Muscle Fibers, Skeletal/cytology, Muscle Fibers, Skeletal/metabolism, Muscle, Skeletal/metabolism, Muscle, Skeletal/pathology, Mutation, Missense, Myasthenic Syndromes, Congenital/genetics, Neuromuscular Junction/genetics, Neuromuscular Junction/metabolism, Pedigree, Protein Structure, Tertiary, Rats, Receptors, Cholinergic/genetics, Receptors, Cholinergic/metabolism, Recombinant Proteins/chemistry, Recombinant Proteins/metabolism, Synapses/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/10/2009 15:49
Dernière modification de la notice
08/05/2019 20:49
Données d'usage