Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction

Ricardo A Maselli, Juan Arredondo, Órla Cagney, Jarae J. Ng, Jennifer A. Anderson, Colette Williams, Bae J. Gerke, Betty Soliven, Robert L. Wollmann

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Abstract

We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies inMuSKdeficientmyotubes revealed that A727V,which is located within the catalytic loop of theenzyme, causedsevere impairment of agrindependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptorrelated protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.

Original languageEnglish (US)
Article numberddq110
Pages (from-to)2370-2379
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2010

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Congenital Myasthenic Syndromes
Receptor Protein-Tyrosine Kinases
Muscles
Mutation
Cholinergic Receptors
Missense Mutation
Agrin
Phosphorylation
Imaginal Discs
Neuromuscular Junction
Microelectrodes
LDL Lipoproteins
Drosophila
Microscopy
Carrier Proteins
Phosphotransferases
Biopsy
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Maselli, R. A., Arredondo, J., Cagney, Ó., Ng, J. J., Anderson, J. A., Williams, C., ... Wollmann, R. L. (2010). Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Human Molecular Genetics, 19(12), 2370-2379. [ddq110]. https://doi.org/10.1093/hmg/ddq110

Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. / Maselli, Ricardo A; Arredondo, Juan; Cagney, Órla; Ng, Jarae J.; Anderson, Jennifer A.; Williams, Colette; Gerke, Bae J.; Soliven, Betty; Wollmann, Robert L.

In: Human Molecular Genetics, Vol. 19, No. 12, ddq110, 15.06.2010, p. 2370-2379.

Research output: Contribution to journalArticle

Maselli, RA, Arredondo, J, Cagney, Ó, Ng, JJ, Anderson, JA, Williams, C, Gerke, BJ, Soliven, B & Wollmann, RL 2010, 'Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction', Human Molecular Genetics, vol. 19, no. 12, ddq110, pp. 2370-2379. https://doi.org/10.1093/hmg/ddq110
Maselli RA, Arredondo J, Cagney Ó, Ng JJ, Anderson JA, Williams C et al. Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Human Molecular Genetics. 2010 Jun 15;19(12):2370-2379. ddq110. https://doi.org/10.1093/hmg/ddq110
Maselli, Ricardo A ; Arredondo, Juan ; Cagney, Órla ; Ng, Jarae J. ; Anderson, Jennifer A. ; Williams, Colette ; Gerke, Bae J. ; Soliven, Betty ; Wollmann, Robert L. / Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 12. pp. 2370-2379.
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