Sleuthing molecular targets for neurological diseases at the neuromuscular junction

The analysis of congenital myasthenic syndromes (CMSs) has disclosed a diverse array of molecular targets at the motor endplate and has delineated their contribution to synaptic function. Clinical, electrophysiological and morphological studies have paved the way for detecting CMS-related mutations in proteins such as choline acetyltransferase, acetylcholinesterase, the acetylcholine receptor and rapsyn, and studies of the mutant proteins have allowed us to correlate the effects of the mutations with predicted alterations in protein structure. Here, we review the symptomatology of CMSs, consider the factors that impair neuromuscular transmission, survey the mutations that have been uncovered in the different synaptic proteins, and consider the functional implications of the identified mutations.