Congenital myasthenic syndrome due to mutations in MUSK suggests that the level of MuSK phosphorylation is crucial for governing synaptic structure.
Adrenergic beta-2 Receptor Agonists
/ pharmacology
Alleles
Amino Acid Substitution
Animals
CRISPR-Cas Systems
Cell Line
DNA Mutational Analysis
Female
Gene Targeting
Humans
Mice
Models, Molecular
Molecular Conformation
Muscle Proteins
/ metabolism
Mutation
Myasthenic Syndromes, Congenital
/ diagnosis
Pedigree
Phosphorylation
Receptor Protein-Tyrosine Kinases
/ chemistry
Receptors, Cholinergic
/ chemistry
Structure-Activity Relationship
Synapses
/ genetics
AChR clustering
MuSK phosphorylation
congenital myasthenic syndromes
dimerization
muscle-specific kinase (MuSK)
neuromuscular junction
receptor tyrosine kinases
β2-adrenergic agonists
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
11
06
2019
revised:
08
09
2019
accepted:
05
11
2019
pubmed:
26
11
2019
medline:
22
7
2021
entrez:
26
11
2019
Statut:
ppublish
Résumé
MUSK encodes the muscle-specific receptor tyrosine kinase (MuSK), a key component of the agrin-LRP4-MuSK-DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early-onset congenital myasthenic syndrome and two novel missense mutations in MUSK (p.C317R and p.A617V). Functional studies show that MUSK p.C317R, located at the frizzled-like cysteine-rich domain of MuSK, disrupts an integral part of MuSK architecture resulting in ablated MuSK phosphorylation and acetylcholine receptor (AChR) cluster formation. MUSK p.A617V, located at the kinase domain of MuSK, enhances MuSK phosphorylation resulting in anomalous AChR cluster formation. The identification and evidence for pathogenicity of MUSK mutations supported the initiation of treatment with β2-adrenergic agonists with a dramatic improvement of muscle strength in the patient. This work suggests uncharacterized mechanisms in which control of the precise level of MuSK phosphorylation is crucial in governing synaptic structure.
Identifiants
pubmed: 31765060
doi: 10.1002/humu.23949
pmc: PMC7028094
doi:
Substances chimiques
Adrenergic beta-2 Receptor Agonists
0
DOK7 protein, human
0
Muscle Proteins
0
Receptors, Cholinergic
0
MUSK protein, human
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
619-631Subventions
Organisme : Medical Research Council
ID : MR/S005382/1
Pays : United Kingdom
Organisme : Austrian Science Fund FWF
ID : P 31199
Pays : Austria
Organisme : Medical Research Council
ID : MR/M006824/1
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.
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