Macroscopic properties of spontaneous mutations in slow-channel syndrome: Correlation by domain and disease severity

Abstract

The slow-channel syndrome (SCS) is a neuromuscular disorder characterized by fatigability, progressive weakness, and degeneration of the neuromuscular junction. The SCS is caused by missense mutations in the four subunits of the skeletal muscle acetylcholine receptor (AChR), which leads to altered channel gating, prolonged neuromuscular postsynaptic currents, and impaired neuromuscular transmission. Although a diverse set of mutations in different functional domains of the AChR appear to be associated with symptoms of widely ranging severity, there is as yet no mutant channel property or combination that explains the variations in disease severity. By observing the recovery time of AChR from desensitization, the authors determined that this process is significantly enhanced in SCS channels. In addition, as expected, the authors found that SCS macroscopic decay currents in transfected HEK293 cells are slower than wild type currents. While slight differences in relative Ca2+ permeability between some SCS mutations were identified, they did not correlate with apparent disease severity. These results suggest that of the different AChR kinetic features studied, only recovery from desensitization and slow postsynaptic currents correlate with the severity observed in the different mutations of this syndrome. © 2006 Wiley-Liss, Inc.