{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:08:52Z","timestamp":1779199732288,"version":"3.51.4"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,25]]},"abstract":"<jats:p>We identify 2 homozygous mutations in the \u03b5-subunit of the muscle acetylcholine receptor (AChR) in 3 patients with severe congenital myasthenia: \u03b5R218W in the pre-M1 region in 2 patients and \u03b5E184K in the \u03b28-\u03b29 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cys-loop receptor superfamily, while Glu184 is conserved in the \u03b1-, \u03b4-, and \u03b5-subunits of AChRs from all species. \u03b5R218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas \u03b5E184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression. Determinations of the effective channel gating rate constants, combined with mutant cycle analyses, demonstrate strong energetic coupling between \u03b5R218 and \u03b5E184, and between \u03b5R218 and \u03b5E45 from the \u03b21-\u03b22 linker, as also observed for equivalent residues in the principal coupling pathway of the \u03b1-subunit. Thus, efficient and rapid gating of the AChR channel is achieved not only by coupling between conserved residues within the principal coupling pathway of the \u03b1-subunit, but also between corresponding residues in the \u03b5-subunit.<\/jats:p>","DOI":"10.1172\/jci.insight.97826","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T11:00:56Z","timestamp":1516791656000},"source":"Crossref","is-referenced-by-count":12,"title":["Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor \u03b5-subunit"],"prefix":"10.1172","volume":"3","author":[{"given":"Xin-Ming","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan M.","family":"Brengman","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuromuscular 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