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

Forty-two missense, truncation, or splice-site mutations of the acetylcholi ne receptor (AChR) subunit genes have been reported to date in patients wit h congenital myasthenic syndromes. Here we report a homozygous mutation, ep silon-155G --> A, in the promoter region of the AChR epsilon subunit gene t hat converts the Ets-binding site of the promoter region from CGGAA to CAGA A. The asymptomatic parents and brother are heterozygous and an affected si ster is homozygous for epsilon-155G --> A. The Ets-binding site mediates sy napse specific expression of the AChR epsilon subunit gene. An identical G- to-A mutation in the mouse Ets-binding site was previously shown to decreas e the binding affinity of the Ets-binding site for the GA binding protein, a transactivating factor for thefts-binding site, and to reduce the synapse specific expression of the epsilon subunit. The decreased synaptic express ion of the epsilon subunit readily accounts for the congenital myasthenic p henotype. (C) 1999 Elsevier Science B.V. All rights reserved.