[Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].
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.
Chevessier
Frédéric
F
INSERM U582 & IFR 14, Institut de Myologie, Hôpital de la Salpêtrière et 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
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
D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases