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

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.

Variable phenotypes associated with mutations in DOK7.

Many patients with the limb-girdle variant of congenital myasthenic syndrome (CMS) possess mutations in the human Dok-7 gene (DOK7). We identified six unrelated CMS patients with DOK7 mutations. Two patients, one mildly and the other moderately affected, were homozygous for the previously described 1263insC mutation.