Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

Julien Oury, Wei Zhang, Nadia Leloup, Akiko Koide, Alexis D. Corrado, Gayatri Ketavarapu, Takamitsu Hattori, Shohei Koide () and Steven J. Burden ()
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Julien Oury: NYU Grossman School of Medicine
Wei Zhang: NYU Grossman School of Medicine
Nadia Leloup: NYU Langone Health
Akiko Koide: NYU Langone Health
Alexis D. Corrado: NYU Langone Health
Gayatri Ketavarapu: NYU Langone Health
Takamitsu Hattori: NYU Langone Health
Shohei Koide: NYU Langone Health
Steven J. Burden: NYU Grossman School of Medicine

Nature, 2021, vol. 595, issue 7867, 404-408

Abstract: Abstract Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.

Date: 2021
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DOI: 10.1038/s41586-021-03672-3

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