Neurology®
The most widely read and highly cited peer-reviewed Neurology journal
Quick Search
Advanced Search
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Correspondence:
Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Correspondence are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shen, X.-M.
Right arrow Articles by Engel, A.G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shen, X.-M.
Right arrow Articles by Engel, A.G.
Related Collections
Right arrow Myasthenia
Right arrow Ion channel gene defects

Neurology 2002;59:1881-1888
© 2002 American Academy of Neurology

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

X.-M. Shen, PhD, K. Ohno, MD PhD, T. Fukudome, MD PhD, A. Tsujino, MD PhD, J.M. Brengman, BS, D.C. De Vivo, MD, R.J. Packer, MD and A.G. Engel, MD

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 {epsilon} subunit; only two mutations have been reported in the AChR {delta} subunit to date.

Methods: Cytochemistry, electron microscopy, {alpha}-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 ({delta}P250Q) of the penultimate proline in the first transmembrane domain (TMD1) of the AChR {delta} subunit. Expression studies indicate that {delta}P250Q (1) hinders {delta}/{alpha} 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 {delta}P250L also has fast-channel effects, whereas {epsilon} P245L and {epsilon} P245Q, identical mutations of the corresponding proline in the {epsilon} subunit, have mild slow-channel effects.

Conclusions: {delta}P250Q represents the third mutation observed in the AChR {delta} subunit. The severe phenotype caused by {delta}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 {delta} and {epsilon} subunits exert a reciprocal regulatory effect on the length of the channel opening bursts reveals an unexpected functional asymmetry between the two subunits.




This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
A. Masuda, X.-M. Shen, M. Ito, T. Matsuura, A. G. Engel, and K. Ohno
hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome
Hum. Mol. Genet., December 15, 2008; 17(24): 4022 - 4035.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Hamuro, O. Higuchi, K. Okada, M. Ueno, S.-i. Iemura, T. Natsume, H. Spearman, D. Beeson, and Y. Yamanashi
Mutations Causing DOK7 Congenital Myasthenia Ablate Functional Motifs in Dok-7
J. Biol. Chem., February 29, 2008; 283(9): 5518 - 5524.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
J. S. Muller, S. K. Baumeister, U. Schara, J. Cossins, S. Krause, M. v. d. Hagen, A. Huebner, R. Webster, D. Beeson, H. Lochmuller, et al.
CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn
Brain, October 1, 2006; 129(10): 2784 - 2793.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
X.-M. Shen, K. Ohno, S. M. Sine, and A. G. Engel
Subunit-specific contribution to agonist binding and channel gating revealed by inherited mutation in muscle acetylcholine receptor M3-M4 linker
Brain, February 1, 2005; 128(2): 345 - 355.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
R. Webster, M. Brydson, R. Croxen, J. Newsom-Davis, A. Vincent, and D. Beeson
Mutation in the AChR ion channel gate underlies a fast channel congenital myasthenic syndrome
Neurology, April 13, 2004; 62(7): 1090 - 1096.
[Abstract] [Full Text] [PDF]