Caractérisation physiopathologique des syndromes myasthéniques congénitaux : l'exemple de mutations dans le gène

Les syndromes myasthéniques congénitaux (SMC) sont des maladies génétiques rares affectant la jonction neuromusculaire (JNM) et caractérisés par un dysfonctionnement de la neurotransmission. Ils forment un ensemble hétérogène sur le plan physiopathologique et peuvent être classés en trois groupes selon leur origine : présynaptique, synaptique ou postsynaptique. Nous rapportons ici pour la première fois que des mutations dans le gène codant pour une molécule postsynaptique, le récepteur tyrosine kinase spécifique du muscle, MuSK, sont responsables d'un SMC postsynaptique. L'analyse génétique a permis d'identifier deux mutations hétéroalléliques, une mutation entraînant un décalage du cadre de lecture (c.220insC) et une mutation faux-sens (V790M). La biopsie musculaire a montré des anomalies importantes à la fois pré et postsynaptiques de la structure de la jonction neuromusculaire et une diminution sévère de l'expression de la sous-unité ε du récepteur de l'acétylcholine (RACh) et de MuSK. Des expériences in vivo et in vitro ont été réalisées en utilisant des mutants de MuSK reproduisant les mutations humaines. La mutation décalant le cadre de lecture conduit à l'absence de l'expression de MuSK. La mutation faux sens n'affecte pas l'activité catalytique kinase de MuSK mais diminue son expression et sa stabilité conduisant à une diminution de l'agrégation du RACh sous la dépendance de l'agrine. Ces résultats suggèrent fortement que la mutation faux sens, en présence de la mutation nulle sur l'autre allèle, est responsable des modifications synaptiques très importantes observées chez le patient

MUSK, a new target for mutations causing congenital myasthenic syndrome

International audienc

Caractérisation physiopathologique des syndromes myasthéniques congénitaux : l'exemple de mutations dans le gène MUSK

International audienc

Correction: A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia.

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

MUSK, a new target for mutations causing congenital myasthenic syndrome

International audienceWe report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding 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

A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia

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