Journal Article

A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia

Schaeffer, Laurent, Leroy, Jean-Paul, Kahrizi, Kimia, Hantaï, Daniel, Taly, Antoine, Herbst, Ruth, Bauché, Stéphanie, Ben Ammar, Asma, Gaudon, Karen, Soltanzadeh, Payam, Ilkhani, Manouchehr, Goillot, Evelyne, Higuchi, Osamu, Koenig, Jeanine, Najmabadi, Hossein, Eymard, Bruno, Yamanashi, Yuji, Hentati, Fayçal, Fardeau, Michel, Richard, Pascale, Huzé, Caroline

2013

Overview

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Agrin / Agrin - metabolism / Animals / Axon sprouting / Biology / Biopsy / Child / Coding / Congenital defects / Consanguinity / Cytochemistry / Denervation / Electron microscopy / Electroporation / Genetic analysis / Genetic aspects / Genetic disorders / Genetics / HEK293 Cells / Human genetics / Humans / Insulin-like growth factors / Kinases / Life Sciences / Male / Medicine / Mice / Missense mutation / Muscle Proteins - genetics / Muscle Proteins - metabolism / Muscle Weakness - genetics / Muscle Weakness - metabolism / Muscle Weakness - physiopathology / Muscle, Skeletal - innervation / Muscle, Skeletal - physiopathology / Muscles / MUSK protein / Mutation / Mutation, Missense / Myasthenia / Myasthenia gravis / Myasthenic Syndromes, Congenital - genetics / Myasthenic Syndromes, Congenital - metabolism / Myasthenic Syndromes, Congenital - physiopathology / Neural coding / Neurobiology / Neuromuscular Junction - genetics / Neuromuscular Junction - metabolism / Neuromuscular Junction - physiopathology / Neuromuscular junctions / Neuromuscular transmission / Neurons and Cognition / Paralysis / Parents / Phosphorylation / Proteins / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - metabolism / Receptors, Cholinergic - genetics / Receptors, Cholinergic - metabolism / Receptors, Growth Factor - genetics / Receptors, Growth Factor - metabolism / Reinnervation / Signal Transduction / Synaptic Transmission - genetics