A common mutation (epsilon 1267delG) in congenital myasthenic patients of Gypsy ethnic origin

Objective: Mutation analysis of the acetylcholine receptor (AChR) epsilon s ubunit gene in patients with sporadic or autosomal recessive congenital mya sthenic syndromes (CMS). Background: The nicotinic AChR of skeletal muscle is a neurotransmitter-gated ion channel that mediates synaptic transmission at the vertebrate neuromuscular junction. Mutations in its gene may cause congenital myasthenic syndromes. A recently described mutation in exon 12 o f the AChR epsilon subunit (epsilon 1267delG) disrupts the cytoplasmic loop and the fourth transmembrane region (M4) of the AChR epsilon subunit. Meth ods: Forty-three CMS patients from 35 nonrelated families were clinically c lassified as sporadic cases of CMS (group III according to European Neuromu scular Centre consensus) and were analyzed for epsilon 1267delG by PCR ampl ification and sequence analysis. Results: The authors report the complete g enomic sequence and organization of the gene coding for the epsilon subunit of the human AChR (accession number AF105999). Homozygous epsilon 1267delG was identified in 13 CMS patients from 11 independent families. All epsilo n 1267delG families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derive fr om a common ancestor (founder) caus ing CMS in the southeastern European Gypsy population. Phenotype analysis r evealed a uniform pattern of clinical features including bilateral ptosis a nd mild to moderate fatigable weakness of ocular,facial, bulbar, and limb m uscles. Conclusions: The mutation epsilon 1267delG might; be frequent in Eu ropean congenital myasthenic syndrome patients of Gypsy ethnic origin. In g eneral, patients (epsilon 1267delG) were characterized by the onset of symp toms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disea se.