title: Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene.
abstract: 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, epsilon-155G --> A, in the promoter region of the AChR epsilon 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 epislon-155G --> A. The Ets-binding site mediates synapse specific expression of the AChR epsilon 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 epsilon subunit. The decreased synaptic expression of the epsilon subunit readily accounts for the congenital myasthenic phenotype.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ohno
authors.forename: B
authors.initials: B
authors.lastname: Anlar
authors.forename: A G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009045:Motor Endplate / Q000235:genetics; D009154:Mutation; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011950:Receptors, Cholinergic; D014157:Transcription Factors; D004247:DNA