A newly identified chromosomal microdeletion and an N-box mutation of the AChR epsilon gene cause a congenital myasthenic syndrome.

Abstract

Congenital myasthenic syndromes (CMSs) are frequently caused by mutations of the coding region of the acetylcholine receptor epsilon subunit (AChRepsilon) 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 AChRepsilon 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 (epsilon-154G-->A) in the N-box of the AChRepsilon promoter in a German CMS pedigree. Semiquantitative analysis of AChRepsilon mRNA levels in the patient's muscle indicated significantly impaired AChRepsilon expression. We provide additional evidence of a pathogenic role for this mutation using the mutated promoter (epsilon-154G-->A) 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 AChRepsilon promoter (epsilon-154G-->A) together with paternal inheritance of a chromosomal microdeletion (Delta1290 bp) encompassing the promoter and the first two exons of the AChRepsilon gene in the index patient. In conclusion, we provide genetic and functional evidence that a mutation of the AChRepsilon subunit promoter (epsilon-154G-->A) 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.

• Authors: Angela Abicht, Rolf Stucka, Carolin Schmidt, Alexandre Briguet, Sebastian Höpfner, In-Ho Song, Dieter Pongratz, Wolfgang Müller-Felber, Markus A Ruegg, Hanns Lochmüller
• Journal: Brain : a journal of neurology (Brain) Vol. 125 Issue Pt 5 Pg. 1005-13 (May 2002) ISSN: 0006-8950 [Print] England
• PMID: 11960891 (Publication Type: Case Reports, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cholinergic

Topics

• Adult
• Animals
• Base Sequence
• Chromosome Deletion
• Female
• Gene Expression Regulation
• Genetic Vectors
• Humans
• Male
• Molecular Sequence Data
• Muscle, Skeletal (metabolism)
• Mutation (genetics)
• Myasthenic Syndromes, Congenital (genetics, metabolism)
• Pedigree
• Polymorphism, Genetic (genetics)
• Promoter Regions, Genetic
• Rats
• Receptors, Cholinergic (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Initiation Site