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SANTE MALADIE MEDECIN MAROC NEUROLOGIE MYASTHENIE HASSAN_II MOHAMMED_VI IDRISSI MAIDOC2 MAIDOC MESTINON MYTELASE TEGELINE IMMUNOGLOBULINES PLASMAPHERESE THYMUS ASSOCIATION |
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Réponse à: Syndrômes myasthéniques : le point sur le MUSK envoi de AAMM- INFOS-MED le 29 Septembre 2005 01:25:59:
INSERM U582 & IFR Cur, Muscle, Vaisseaux, Institut de Myologie, Hopital de la Salpetriere and Universite Pierre et Marie Curie, Paris, France.
We 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.
PMID: 15496425 [PubMed - indexed for MEDLINE]