Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene

Objective: To identify and to characterize functionally the mutational basi s of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Backgr ound: A total of 37 patients belonging to 13 CMS families, 9 of them consan guineous, were investigated. All patients were linked previously to the tel omeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acet ylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene re vealed no mutations. The authors thus searched for mutations in the epsilon -subunit gene of AChR. Methods: Direct sequencing of the AChR epsilon-subun it, restriction analysis, allele-specific PCR, and expression studies in hu man embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncat ing (epsilon 723delC and epsilon 760ins8), one is a missense mutation in th e signal peptide region (epsilon V-13D), one is a missense mutation in the N-terminal extracellular domain (epsilon T51P), and one is a splice donor s ite mutation in intron 10 (epsilon IVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that th e four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expre ssor or null mutations. Conclusions: Chromosome 17p-linked congenital myast henic syndromes are caused by low-expressor/null mutations in the AChR epsi lon-subunit gene. Mutations in this gene are a common cause of CMS in easte rn Mediterranean countries.