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) All Versions of this Article: 01.wnl.0000233837.79459.40v1 67/7/1159    most recent 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 Google Scholar Google Scholar Articles by Müller, J. S. Articles by Lochmüller, H. Search for Related Content PubMed PubMed Citation Articles by Müller, J. S. Articles by Lochmüller, H. Related Collections Myasthenia All Genetics

Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations

From Friedrich-Baur-Institute, Department of Neurology (J.S.M., S.K.B., S.K., W.M.-F., A.A., H.L.), and University Childrens Hospital, Department of Neuropediatrics (K.K.), Ludwig-Maximilians-University, Munich, Germany; and Clinic for Child Neurology and Psychiatry (V.M.R., S.T.), University of Belgrade, Serbia and Montenegro.

Address correspondence and reprint requests to Dr. Hanns Lochmüller, Friedrich-Baur-Institute, Marchioninistr. 17, 81377 München, Germany; e-mail: Hanns.Lochmueller{at}med.uni-muenchen.de

Objective: Congenital myasthenic syndromes (CMS) with underlying RAPSN mutations turned out to be of high clinical relevance due to their worldwide frequency. To date, all reported patients with CMS with sequence variations in the translated region of RAPSN carry the mutation N88K on at least one allele. The authors report two patients lacking the common N88K allele but harboring differing novel mutations of the RAPSN gene on both alleles: one patient is homozygous for a missense mutation (R164C); the second patient is compound heterozygous for a splice (IVS1-15C>A) and another missense mutation (L283P).

Methods: The authors analyzed the RAPSN gene for sequence variations and carried out in vitro studies in order to delineate the potential pathogenicity of the three novel RAPSN mutations.

Results: For the putative splice mutation (IVS1-15C>A), the authors constructed wild-type and mutated RAPSN minigenes for transfection and subsequent RNA analysis. The mutation generates a novel acceptor splice site leading to retention of 13 nucleotides of intron 1 in the mature mRNA and subsequently to a frameshift transcript. Cotransfection of wild-type AChR subunits with RAPSN-constructs carrying R164C and L283P indicate that both mutations diminish coclustering of AChR with rapsyn.

Conclusions: Screening for the common mutation RAPSN N88K facilitates targeted genetic analysis in congenital myasthenic syndromes. However, absence of a N88K allele does not exclude underlying RAPSN mutations as cause of the congenital myasthenic syndromes. Sequencing of the entire gene may be considered in patients with joint contractures and respiratory problems even in the absence of the mutation N88K.

This article was previously published in electronic format as an Expedited E-Pub on August 23, 2006, at www.neurology.org.

*These authors contributed equally.

Supported by grants from the Association Francaise contre les Myopathies (AFM) to H.L., A.A., and J.S.M.

Disclosure: The authors report no conflicts of interest.

Received January 10, 2006. Accepted in final form June 2, 2006.