Titre : | A human mutation in musk causes its constitutive activation and is responsible for a congenital myasthenic syndrome : Acte de colloque : 4ème colloque international de Myologie (9-13 mai 2011; Lille (France)) |
contenu dans : | |
Auteurs : | Ben Ammar A ; Soltanzadeh P ; Bauche S ; Richard P ; Goillot E ; Herbst R ; Gaudon K ; Huze C ; Lecuyer HA ; Schaeffer L ; Yamanashi Y ; Higuchi O ; Taly A ; Koenig J ; Leroy JP ; Hentati F ; Najmabadi H ; Kahrizi K ; Ilkhani M ; Fardeau M ; Eymard B ; Hantaï D |
Type de document : | Article |
Editeur : | AFM-TELETHON, 2011 |
Pages : | p 58 |
Langues: | Anglais |
Mots-clés : | colloque ; syndrome myasthénique congénital |
Résumé : |
Poster :
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, a novel MuSK mutation identified and the pathogenic consequences of this mutation experimentally explored.Genetic analysis of the patient and morphological analysis of his NMJs on biopsied deltoid muscle were performed. Mutated MuSK cDNA was transfected in cultured cells as well as in mouse muscle. In cells, agrin-dependent acetylcholine receptor aggregation, Dok7- and agrin-dependent MuSK phosphorylation were explored. In mouse muscle immunocytochemical and electron microscopic analysis of the NMJs was performed.Genetic analysis revealed a consanguineous homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. Dramatic changes in pre- and post-synaptic elements of the NMJs were observed in biopsied muscle. These changes induced a process of denervation / reinnervation in native NMJs and the appearance of newly formed NMJs. In vivo electroporation of the mutated MuSK in mouse muscle showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy. In vitro experiments showed that the mutation causes MuSK phosphorylation even in the absence of agrin and a decrease in Dok-7-dependent phosphorylation.These findings further implicate MuSK in the pathogeny of CMS and this takes place through a novel mechanism of constitutive MuSK phosphorylation.This work was supported by APHP, Raux Inserm, ANR-Maladies Rares, AFM, and Comitxte Franco-Tunisien pour la Cooption Universitaire. P.S. was the recipient of a postdoctoral fellowship from the AFM. |