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

X. M. Shen, K. Ohno, T. Fukudome, A. Tsujino, J. M. Brengman, D. C. De Vivo, R. J. Packer, Andrew G. Engel

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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 ε subunit; only two mutations have been reported in the AChR δ subunit to date. Methods: Cytochemistry, electron microscopy, α-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 (δP250Q) of the penultimate proline in the first transmembrane domain (TMD1) of the AChR δ subunit. Expression studies indicate that δP250Q (1) hinders δ/α 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 δP250L also has fast-channel effects, whereas ε P245L and ε P245Q, identical mutations of the corresponding proline in the ε subunit, have mild slow-channel effects. Conclusions: εP250Q represents the third mutation observed in the AChR δ subunit. The severe phenotype caused by δP250Q 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 δ and ε subunits exert a reciprocal regulatory effect on the length of the channel opening bursts reveals an unexpected functional asymmetry between the two subunits.

Original languageEnglish (US)
Pages (from-to)1881-1888
Number of pages8
Issue number12
StatePublished - Dec 24 2002

ASJC Scopus subject areas

  • Clinical Neurology


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