MUSK, a new target for mutations causing congenital myasthenic syndrome - Archive ouverte HAL Access content directly
Journal Articles Human Molecular Genetics Year : 2004

MUSK, a new target for mutations causing congenital myasthenic syndrome

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Abstract

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.

Dates and versions

hal-03863846 , version 1 (21-11-2022)

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Frédéric Chevessier, Brice Faraut, Aymeric Ravel-Chapuis, Pascale Richard, Karen Gaudon, et al.. MUSK, a new target for mutations causing congenital myasthenic syndrome. Human Molecular Genetics, 2004, 13 (24), pp.3229-3240. ⟨10.1093/hmg/ddh333⟩. ⟨hal-03863846⟩
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