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REVIEW : Molecular Basis of Congenital Myasthenic Syndromes: Mutations in the Acetylcholine Receptor

Muscle Research Laboratory and Department of Neurology, Mayo Clinic and Mayo Foundation Rochester, Minnesota

Kinji Ohno

Muscle Research Laboratory and Department of Neurology, Mayo Clinic and Mayo Foundation Rochester, Minnesota

Hai-Long Wang

Department of Physiology and Biophysics and Receptor Biology Laboratory Mayo Clinic and Mayo Foundation Rochester, Minnesota

Margherita Milone

Muscle Research Laboratory and Department of Neurology, Mayo Clinic and Mayo Foundation Rochester, Minnesota

Steven M. Sine

Department of Physiology and Biophysics and Receptor Biology Laboratory Mayo Clinic and Mayo Foundation Rochester, Minnesota

The congenital myasthenic syndromes include end-plate (EP) acetylcholinesterase deficiency, presynaptic abnormalities affecting the evoked release or size of transmitter quanta, and acetylcholine (ACh) receptor (AChR) channelopathies stemming from a kinetic abnormality and/or deficiency of AChR. A kinetic abnor mality predicts, and AChR deficiency may predict, one or more mutations in an AChR subunit gene. These clues have led to the identification of 53 mutations in different subunits of AChR in 55 kinships of the congenital myasthenic syndromes. The mutations either increase or decrease the response to ACh, produce AChR deficiency, or both. In the slow-channel syndromes, prolonged opening episodes of AChR cause cationic overloading of the EP and an EP myopathy; the mutations occur in different subunits and different domains of the subunits and have dominant positive effects. The M1 and M2 mutations slow channel closure, increase apparent affinity for ACh, and variably enhance desensitization, and the extracellular G153S enhances affinity for ACh, promoting reopening of the diliganded receptor. In the low-affinity fast-channel syndrome, P121L reduces affinity for ACh and reopening of the diliganded receptor, resulting in a de creased response to ACh and shorter burst durations. Severe EP AChR deficiency results from heterozy gous or homozygous mutations that terminate translation prematurely; these are concentrated in the subunit, probably because substitution of the fetal for the adult subunit can rescue the phenotype from fatal null mutations in . Variable AChR deficiency and variable functional abnormalities stem from hetero allelic nonsense and missense mutations in AChR subunit genes. NEUROSCIENTIST 4:185-194, 1998

Key Words: KEY WORDS Neuromuscular junction • Congenital myasthenic syndromes • Acetylcholine receptor • Mutation analysis • Patch-clamp anal ysis

The Neuroscientist, Vol. 4, No. 3, 185-194 (1998)
DOI: 10.1177/107385849800400314


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