MUSK, a new target for mutations causing congenital myasthenic syndrome
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.
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MUSK is implicated in congenital myasthenic syndrome.
“These Neanderthal introgression signals span the gene MUSK, which is implicated in congenital myasthenic syndrome (Fig. 3d) [37].”
From A refined analysis of Neanderthal-introgressed sequences in modern humans with a complete reference genome (2025) · cites this paper as [37]
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- Authors
- Chevessier, F., Faraut, B., Ravel-Chapuis, A., Richard, P., Gaudon, K., Bauché, S., Prioleau, C., Herbst, R., Goillot, E., Ioos, C., Azulay, J.-P., Attarian, S., Leroy, J.-P., Fournier, E., Legay, C., Schaeffer, L., Koenig, J., Fardeau, M., Eymard, B., Pouget, J., & Hantaï, D.
- Affiliations
- Inserm (FR)
- Medical University of Vienna (AT)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Corresponding author
- Chevessier, Frédéric
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-10-20
- Volume
- 13
- Issue
- 24
- Pages
- 3229-3240
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2119148360
- Cited by
- 193
- References
- 35
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 2 · 2016: 8 · 2015: 10 · 2014: 8 · 2013: 15 · 2012: 12
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Myasthenia Gravis and Thymoma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- congenital myasthenic syndrome, musk, neuromuscular junction, acetylcholine receptor epsilon subunit, frameshift mutation, missense mutations, neuromuscular transmission, axon growth
- MeSH terms
- Adult, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Male, Muscles, Mutation, Pedigree, Polymorphism, Genetic, Receptors, Cholinergic, Myasthenic Syndromes, Congenital, Receptor Protein-Tyrosine Kinases
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