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Congenital myasthenic syndrome caused by low-expressor fast-channel AChR subunit mutation

From the Department of Neurology and Neuromuscular Research Laboratory (Drs. Shen, Ohno, Fukudome, Tsujino, and Engel, and J.M. Brengman), Mayo Clinic, Rochester, MN; the Department of Neurology (Dr. De Vivo), Columbia University, New York, NY; and Children’s National Medical Center (Dr. Packer), Washington, D.C.

Address correspondence and reprint requests to Dr. Andrew G. Engel, Department of Neurology, Mayo Clinic, Rochester, MN, 55905; e-mail: age{at}mayo.edu

Objective: To determine the molecular basis of a disabling congenital myasthenic syndrome (CMS) observed in two related and one unrelated Arab kinship.

Background: CMS can arise from defects in presynaptic, synaptic basal lamina–associated, or postsynaptic proteins. Most CMS are postsynaptic, and most reside in the AChR subunit; only two mutations have been reported in the AChR subunit to date.

Methods: Cytochemistry, electron microscopy, -bungarotoxin binding studies, microelectrode and patch-clamp recordings, mutation analysis, mutagenesis, and expression studies in human embryonic kidney cells were employed.

Results: Endplate studies showed AChR deficiency, fast decaying, low-amplitude endplate currents, and abnormally brief channel opening events. Mutation analysis revealed a novel homozygous missense mutation (P250Q) of the penultimate proline in the first transmembrane domain (TMD1) of the AChR subunit. Expression studies indicate that P250Q (1) hinders / subunit association during early AChR assembly; (2) hinders opening of the doubly occupied closed receptor (A₂R); and (3) speeds the dissociation of acetylcholine from A₂R. Mutagenesis studies indicate that P250L also has fast-channel effects, whereas P245L and P245Q, identical mutations of the corresponding proline in the subunit, have mild slow-channel effects.

Conclusions: P250Q represents the third mutation observed in the AChR subunit. The severe phenotype caused by P250Q is attributed to endplate AChR deficiency, fast decay of the synaptic response, and lack of compensatory factors. That the penultimate prolines in TMD1 of the and subunits exert a reciprocal regulatory effect on the length of the channel opening bursts reveals an unexpected functional asymmetry between the two subunits.

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