Mutations causing muscle weakness

Transmission of signals from nerves to muscles is critical for life, so substantial safety factor mechanisms have evolved to ensure its success. Despite this, diseases can impair even this robust system. Characterizing these disease mechanisms greatly contributes to understanding this fundamental process. Neuromuscular transmission serves as a model for helping to understand neurotransmission throughout the nervous system. Mutations in critical components of the neuromuscular junction or autoimmune responses to them cause muscle weakness and fatigability termed “myasthenia.”

More than 20 years ago, Andrew Engel and his co-workers began to identify congenital myasthenic syndromes (reviewed in ref. 1). Syndromes were found that reflected deficits in almost every step of neuromuscular transmission: reduced numbers of synaptic vesicles of acetylcholine (ACh), reduced evoked release of vesicles, defective synthesis or packaging of ACh, deficiency of acetylcholinesterase (AChE), deficiency of ACh receptors (AChRs), and altered AChR function. Clinical characterizations of the patients were followed by biochemical, electrophysiological, and electron microscopic characterization of biopsies containing neuromuscular junctions. Now several critical synaptic components have been cloned and their structures have been determined in some detail. This has led to a remarkable series of papers in which Engel and his co-workers have identified patients with mutations in subunits of their AChRs, transfected cells with mutated AChRs, elegantly characterized their properties, then provided a detailed explanation of the complex effects of these mutations on the patient’s neuromuscular transmission (1). These AChR mutations will be briefly considered again later.

One of the congenital myasthenic syndromes that Engel identified revealed a virtual absence of AChE at neuromuscular junctions. The catalytic subunit of AChE has been cloned and its structure has been determined by x-ray crystallography (2). However, these patients revealed no mutations in the catalytic subunit (3). This mystery is now solved. In this issue of the Proceedings (4), Engel and …