title: [Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].
abstract: Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.
authors.affiliation: INSERM U582 & IFR 14, Institut de Myologie, Hôpital de la Salpêtrière et Université Pierre et Marie Curie, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chevessier
authors.forename: Brice
authors.initials: B
authors.lastname: Faraut
authors.forename: Aymeric
authors.initials: A
authors.lastname: Ravel-Chapuis
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Karen
authors.initials: K
authors.lastname: Gaudon
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bauché
authors.forename: Cassandra
authors.initials: C
authors.lastname: Prioleau
authors.forename: Ruth
authors.initials: R
authors.lastname: Herbst
authors.forename: Evelyne
authors.initials: E
authors.lastname: Goillot
authors.forename: Christine
authors.initials: C
authors.lastname: Ioos
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Azulay
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Leroy
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.forename: Claire
authors.initials: C
authors.lastname: Legay
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.forename: Jeanine
authors.initials: J
authors.lastname: Koenig
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D014162:Transfection
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases