title: A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.
abstract: 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.
authors: Inserm, UMRS 975, UPMC, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors: Asma
authors: A
authors: Ben Ammar
authors: Payam
authors: P
authors: Soltanzadeh
authors: Stéphanie
authors: S
authors: Bauché
authors: Pascale
authors: P
authors: Richard
authors: Evelyne
authors: E
authors: Goillot
authors: Ruth
authors: R
authors: Herbst
authors: Karen
authors: K
authors: Gaudon
authors: Caroline
authors: C
authors: Huzé
authors: Laurent
authors: L
authors: Schaeffer
authors: Yuji
authors: Y
authors: Yamanashi
authors: Osamu
authors: O
authors: Higuchi
authors: Antoine
authors: A
authors: Taly
authors: Jeanine
authors: J
authors: Koenig
authors: Jean-Paul
authors: JP
authors: Leroy
authors: Fayçal
authors: F
authors: Hentati
authors: Hossein
authors: H
authors: Najmabadi
authors: Kimia
authors: K
authors: Kahrizi
authors: Manouchehr
authors: M
authors: Ilkhani
authors: Michel
authors: M
authors: Fardeau
authors: Bruno
authors: B
authors: Eymard
authors: Daniel
authors: D
authors: Hantaï
mesh_terms: D018171:Agrin / Q000378:metabolism; D000818:Animals; D002648:Child; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D018171:Agrin; C511692:DOK7 protein, human; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D017978:Receptors, Growth Factor; C080030:agrin receptor; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases