A synonymous CHRNE mutation responsible for an aberrant splicing leading to congenital myasthenic syndrome.

Congenital myasthenic syndromes (CMSs) are rare hereditary disorders transmitted in a recessive or dominant pattern, and are caused by mutations in the genes encoding proteins of the neuromuscular junction. They are classified in three groups depending on the origin of the molecular defect. Postsynaptic defects are the most frequent and have been reported to be partly due to abnormalities of the acetylcholine receptor, and particularly to mutations in CHRNE, the gene encoding the acetylcholine receptor epsilon-subunit. In a Portuguese patient with a mild form of recessive CMS, CHRNE sequencing identified an unknown homozygous transition. This variation affects the third nucleotide of the glycine 285 condon, and leads to a synonymous variant. Analysis of transcripts demonstrated that this single change creates a new splice donor site located 4 nucleotides upstream of the normal site, leading to a deletion and generating a frameshift in exon 9 followed by a premature termination codon. This paper relates the identification of a synonymous mutation in CHRNE that creates a new splice donor site leading to an aberrant splicing of pre-mRNAs and so to their instability. This is the first synonymous mutation in CHRNE known to generate a cryptic splice site, and mRNA quantification strongly suggests that it is the disease-causing mutation.