MUSK, a new target for mutations causing congenital myasthenic syndrome.
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.
Chevessier
Frédéric
F
INSERM U582 & IFR Cur, Muscle, Vaisseaux, Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France.
Faraut
Brice
B
Ravel-Chapuis
Aymeric
A
Richard
Pascale
P
Gaudon
Karen
K
Bauché
Stéphanie
S
Prioleau
Cassandra
C
Herbst
Ruth
R
Goillot
Evelyne
E
Ioos
Christine
C
Azulay
Jean-Philippe
JP
Attarian
Shahram
S
Leroy
Jean-Paul
JP
Fournier
Emmanuel
E
Legay
Claire
C
Schaeffer
Laurent
L
Koenig
Jeanine
J
Fardeau
Michel
M
Eymard
Bruno
B
Pouget
Jean
J
Hantaï
Daniel
D
D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011110:Polymorphism, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism
D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases