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

Full 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 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.

Author information

Author/s: Huzé, Caroline (C); Bauché, Stéphanie (S); Richard, Pascale (P); Chevessier, Frédéric (F); Goillot, Evelyne (E); Gaudon, Karen (K); Ben Ammar, Asma (A); Chaboud, Annie (A); Grosjean, Isabelle (I); Lecuyer, Heba-Aude (HA); Bernard, Véronique (V); Rouche, Andrée (A); Alexandri, Nektaria (N); Kuntzer, Thierry (T); Fardeau, Michel (M); Fournier, Emmanuel (E); Brancaccio, Andrea (A); Rüegg, Markus A (MA); Koenig, Jeanine (J); Eymard, Bruno (B); Schaeffer, Laurent (L); Hantaï, Daniel (D);

Affiliation: Equipe Différenciation Neuromusculaire, UMR 5239, Ecole Normale Supérieure Lyon, CNRS, Université Lyon 1, Lyon, France.

Journal and publication information

Publication Type: Case Reports; Journal Article; Research Support, Non-U.S. Gov't

Journal: American journal of human genetics (Am J Hum Genet), published in United States. (Language: eng)

Reference: 2009-Aug; vol 85 (issue 2) : pp 155-67

Dates: Created 2009/08/14; Completed 2009/09/23; Revised 2009/11/03;

PMID: 19631309, status: MEDLINE (last retrieval date: 11/4/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

ErratumIn: Am J Hum Genet. 2009 Oct;85(4):536.

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