Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor ε subunit gene

Forty-two missense, truncation, or splice-site mutations of the acetylcholine receptor (AChR) subunit genes have been reported to date in patients with congenital myasthenic syndromes. Here we report a homozygous mutation, ε-155G→A, in the promoter region of the AChR ε subunit gene that converts the Ets-binding site of the promoter region from CGGAA to CAGAA. The asymptomatic parents and brother are heterozygous and an affected sister is homozygous for ε-155G→A. The Ets-binding site mediates synapse specific expression of the AChR ε subunit gene. An identical G-to-A mutation in the mouse Ets-binding site was previously shown to decrease the binding affinity of the Ets-binding site for the GA binding protein, a transactivating factor for the Ets-binding site, and to reduce the synapse specific expression of the ε subunit. The decreased synaptic expression of the ε subunit readily accounts for the congenital myasthenic phenotype. Copyright (C) 1999 Elsevier Science B.V.