A common mutation (ε1267delG) in congenital myasthenic patients of Gypsy ethnic origin

Objective: Mutation analysis of the acetylcholine receptor (AChR) epsilon subunit gene in patients with sporadic or autosomal recessive congenital myasthenic 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 of the AChR epsilon subunit (epsilon 1267delG) disrupts the cytoplasmic loop and the fourth transmembrane region (M4) of the AChR epsilon subunit. Methods: Forty-three CMS patients from 35 nonrelated families were clinically classified as sporadic cases of CMS (group III according to European Neuromuscular Centre consensus) and were analyzed for epsilon 1267delG by PCR amplification and sequence analysis. Results: The authors report the complete genomic 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 epsilon 1267delG families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derive fr om a common ancestor (founder) causing CMS in the southeastern European Gypsy population. Phenotype analysis revealed a uniform pattern of clinical features including bilateral ptosis and mild to moderate fatigable weakness of ocular,facial, bulbar, and limb muscles. Conclusions: The mutation epsilon 1267delG might; be frequent in European congenital myasthenic syndrome patients of Gypsy ethnic origin. In general, patients (epsilon 1267delG) were characterized by the onset of symptoms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disease.