Brain, Vol. 125, No. 5, 1005-1013,
May 2002
© 2002 Guarantors of Brain
A newly identified chromosomal microdeletion and an N-box mutation of the AChR
gene cause a congenital myasthenic syndrome
1 Genzentrum and Friedrich-Baur-Institut, Ludwig-Maximilians-University Munich, Germany and 2 Department of Pharmacology/Neurobiology, Biozentrum, University of Basel, Switzerland
Correspondence to: H. Lochmüller, Genzentrum München, Feodor-Lynen-Strasse 25, 81377 München, Germany E-mail: hanns{at}lmb.uni-muenchen.de
*These authors contributed equally to this work
Congenital myasthenic syndromes (CMSs) are frequently caused by mutations of the coding region of the acetylcholine receptor epsilon subunit (AChR
) gene leading to a reduced expression of the acetylcholine receptor (AChR) at the postsynaptic membrane. Two recent observations have linked two different N-box mutations of the human AChR promoter to a clinical CMS phenotype. N-boxes are regulatory sequence elements of mammalian promoters that confer synapse-specific expression of several genes, including the AChR subunit genes. Here, we report on a novel point mutation (-154G
A) in the N-box of the AChR promoter in a German CMS pedigree. Semiquantitative analysis of AChR mRNA levels in the patient’s muscle indicated significantly impaired AChR expression. We provide additional evidence of a pathogenic role for this mutation using the mutated promoter (-154GA) driving a heterologous gene (luciferase) in rat skeletal muscle. We show that agrin-induced gene expression is significantly reduced by the N-box mutant (mt) compared with the wild-type (wt) promoter. Refined haplotype analysis and direct sequencing revealed maternal inheritance of the mutant AChR promoter (-154GA) together with paternal inheritance of a chromosomal microdeletion (
1290 bp) encompassing the promoter and the first two exons of the AChR gene in the index patient. In conclusion, we provide genetic and functional evidence that a mutation of the AChR subunit promoter (-154GA) causes CMS due to the reduction of gene expression in skeletal muscle. Moreover, this is the first report of a chromosomal microdeletion affecting an AChR gene. This type of mutation may be missed in standard screening techniques of CMS patients.
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