Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

<jats:title>Abstract</jats:title><jats:p>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 CM<jats:sup>1,2</jats:sup>. The most common disease-causing mutation (<jats:italic>DOK7</jats:italic><jats:sup><jats:italic>1124_1127 dup</jats:italic></jats:sup>) 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 (<jats:italic>Dok7</jats:italic><jats:sup><jats:italic>CM</jats:italic></jats:sup> mice) and a mouse with point mutations in the two tyrosine residues (<jats:italic>Dok7</jats:italic><jats:sup><jats:italic>2YF</jats:italic></jats:sup>). We show that <jats:italic>Dok7</jats:italic><jats:sup><jats:italic>CM</jats:italic></jats:sup> 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 <jats:italic>Dok7</jats:italic><jats:sup><jats:italic>CM</jats:italic></jats:sup> mice. These findings identify an unexpected cause for disease and a potential therapy for both <jats:italic>DOK7</jats:italic> CM and other forms of CM caused by mutations in <jats:italic>AGRIN</jats:italic>, <jats:italic>LRP4</jats:italic> or <jats:italic>MUSK</jats:italic>, and illustrate the potential of targeted therapy to rescue congenital lethality.</jats:p>