HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Webster, R. Articles by Beeson, D. Search for Related Content PubMed PubMed Citation Articles by Webster, R. Articles by Beeson, D. Related Collections Amyotrophic lateral sclerosis Ion channel gene defects

Mutation in the AChR ion channel gate underlies a fast channel congenital myasthenic syndrome

From the Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.

Address correspondence and reprint requests to Dr. D. Beeson, Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK; e-mail: dbeeson{at}hammer.imm.ox.ac.uk

Background: Most congenital myasthenic syndromes (CMS) have postsynaptic defects from mutations within the muscle acetylcholine receptor (AChR). Mutations underlying the slow channel syndrome cause a "gain of function" and usually show dominant inheritance, whereas mutations underlying AChR deficiency or the fast channel syndrome cause a "loss of function" and show recessive inheritance.

Objective: To characterize the disease mechanism underlying an apparently dominantly inherited CMS that responds to IV edrophonium.

Methods: DNA from CMS patients was analyzed for mutations by single-strand conformation polymorphism analysis, DNA sequence analysis, and restriction endonuclease digestion. Functional analysis of mutations was by -bungarotoxin binding studies and by patch clamp analysis of mutant AChR expressed in human embryonic kidney cells.

Results: Analysis of muscle biopsies from father and son in an affected kinship showed normal endplate morphology and AChR number but severely reduced miniature endplate potentials. DNA analysis revealed that each harbors a single missense mutation in the AChR -subunit gene, F256L. Expression studies demonstrate this mutation underlies a fast channel phenotype with fewer and shorter ion channel activations. The major effect of F256L, located within the M2 transmembrane domain, is on channel gating, both reducing the opening and increasing the closure rate.

Conclusions: Mutation F256L results in fast channel kinetics. Expression studies suggest a dominant-negative effect within the AChR pentamer, severely compromising receptor function.

Received June 27, 2003. Accepted in final form November 26, 2003.

This article has been cited by other articles:

				Congenital Myasthenic Syndrome: A Mutation That Goes Against the Rules Journal Watch Neurology, July 9, 2004; 2004(709): 4 - 4. [Full Text]