MUSK, a new target for mutations causing congenital myasthenic syndrome
Frédéric Chevessier
(1, 2, 3)
,
Brice Faraut
(1, 2, 3)
,
Aymeric Ravel-Chapuis
(4, 5)
,
Pascale Richard
(6, 1, 2, 3)
,
Karen Gaudon
(6, 1, 2, 3)
,
Stéphanie Bauché
(1, 2, 3)
,
Cassandra Prioleau
(1, 3, 2)
,
Ruth Herbst
(7)
,
Evelyne Goillot
(4, 5)
,
Christine Ioos
(1, 3, 2)
,
Jean-Philippe Azulay
(8, 9)
,
Shahram Attarian
(8, 9)
,
Jean-Paul Leroy
(1, 2, 3, 10)
,
Emmanuel Fournier
(6)
,
Claire Legay
(11)
,
Laurent Schaeffer
(4, 5)
,
Jeanine Koenig
(1, 12, 2, 3)
,
Michel Fardeau
(1, 2, 3)
,
Bruno Eymard
(1, 2, 3)
,
Jean Pouget
(8, 9)
,
Daniel Hantaï
(1, 2, 3)
1
Physiopathologie et thérapie du muscle strié
2 Coeur, Muscle et Vaisseaux
3 Institut de Myologie
4 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
5 BLG - BioSciences Lyon-Gerland
6 CHU Pitié-Salpêtrière [AP-HP]
7 Center for Brain Research [Vienna, Austria]
8 TIMONE - Hôpital de la Timone [CHU - APHM]
9 SCC - Sciences du cerveau et de la cognition
10 CHU - BREST - Hôpital Morvan - CHRU de Brest
11 NEURO - Laboratoire de Neurobiologie (UMR 8544)
12 Université Bordeaux Segalen - Bordeaux 2
2 Coeur, Muscle et Vaisseaux
3 Institut de Myologie
4 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
5 BLG - BioSciences Lyon-Gerland
6 CHU Pitié-Salpêtrière [AP-HP]
7 Center for Brain Research [Vienna, Austria]
8 TIMONE - Hôpital de la Timone [CHU - APHM]
9 SCC - Sciences du cerveau et de la cognition
10 CHU - BREST - Hôpital Morvan - CHRU de Brest
11 NEURO - Laboratoire de Neurobiologie (UMR 8544)
12 Université Bordeaux Segalen - Bordeaux 2
Stéphanie Bauché
- Fonction : Auteur
- PersonId : 169892
- IdHAL : stephanie-godard-bauche
- ORCID : 0000-0002-6926-339X
- IdRef : 203658213
Christine Ioos
- Fonction : Auteur
- PersonId : 902591
Shahram Attarian
- Fonction : Auteur
- PersonId : 1042088
Claire Legay
- Fonction : Auteur
- PersonId : 1248468
- ORCID : 0000-0003-0263-9257
- IdRef : 084436387
Résumé
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.