New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome

ENGEL, A.; OHNO, K.; MILONE, M.; WANG, H-L.; NAKANO, S.; BOUZAT, C.; PRUITT, J.N.; HUTCHINSON, D.O.; BRENGMAN, J.N.; BREN, N.; SIEB, J.P.; SINE, S.M.

HUMAN MOLECULAR GENETICS

OXFORD UNIV PRESS

Año: 1996 vol. 55 p. 1217 - 1227

0964-6906

Mutations in genes encoding the e, d, b and a subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: eL269F and dQ267E in Patient 1, bV266M in Patient 2, and aN217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations. eL269F, dQ267E and bV266M occur in the second and aN217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but dQ267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR. eL269F, bV266M, and aN217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; eL269F and aN217K enhance desensitization, and eL269F and bV266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky. dQ267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate  potentials at physiologic rates of stimulation.