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

Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the ε-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the ε- subunit gene of AChR. Methods: Direct sequencing of the AChR ε-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel ε-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (ε723delC and ε760ins8), one is a missense mutation in the signal peptide region (εV-13D), one is a missense mutation in the N-terminal extracellular domain (εT51P), and one is a splice donor site mutation in intron 10 (εIVS10+2T→G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the 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-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR ε-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.