Diverse aspects of vulnerability at the neuromuscular junction.

Neuromuscular junctions provide the essential link between the nervous system and muscles. In healthy humans, neuromuscular junctions reliably convert every impulse in a motor neuron into a corresponding action potential in each muscle fibre innervated by that particular motor neuron. However, the structural and molecular complexity of neuromuscular junctions means that they contain many potential targets for deleterious mutations. In addition, their location at the relatively unprotected periphery of the nervous system heightens the vulnerability of neuromuscular junctions to injury from a variety of chemical and mechanical agents. Detailed investigations of patients with impaired neuromuscular transmission have provided important insights into how a variety of pathological processes may conspire to impair neuromuscular transmission. The reliability of neuromuscular transmission depends both on how much acetylcholine is released from the nerve terminal and how it acts to excite the muscle fibre membrane (Slater, 2008). Two papers in this issue of Brain add to the list of myasthenic conditions in which the action of acetylcholine is impaired (Klooster et al., 2012; Webster et al., 2012). Taken together, these results emphasize that effectiveness of the transmitter depends on both the detailed molecular properties of the ion channels at the core of the acetylcholine receptors (AChRs) and how many of those receptors are within the range of transmitter molecules released from the nerve terminal. In recent years, many mutations have been found in genes encoding key proteins at neuromuscular junctions that account for inherited defects of neuromuscular transmission, conditions known collectively as congenital myasthenic syndromes (Engel et al., 2010). The targets of these mutations are often the genes encoding the five homologous subunits of the AChR itself. Most of these mutations affect either the detailed kinetics of the opening and closing of ion channels gated by acetylcholine or the abundance of AChR. The paper by Webster et al. (2012) describes an adult patient with lifelong weakness of a number of muscle groups. EMG studies confirmed an impairment of neuromuscular transmission. Sequence analysis of the patient's DNA revealed two mutations of the gene encoding the epsilon subunit ("-) of the AChR, each in a different copy of the gene. One mutation (deletion, p."F266), when present in AChRs expressed in cultured human embyonic kidney (HEK) 293 cells, has little effect on AChR channel kinetics but reduces the flow of current through the open channels to 60% of its normal value. The mutation results in the deletion of …