Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia

Abstract

Objective: To dissect the kinetic defects of acetylcholine receptor (AChR) c subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR e subunit in a congenital myasthenic syndrome (CMS). Methods: Whole exome sequencing, a-bungarotoxin binding assay, single channel patch-clamp recordings, and maximum likelihood analysis of channel kinetics. Results: We identified compound heterozygous variants in AChR c and e subunits in three Escobar syndrome (1-3) and three CMS patients (4-6), respectively. Each Escobar syndrome patient carries cP121R along with cV221Afs*44 in patients 1 and 2, and cY63* in patient 3. Three CMS patients share eP121T along with eR20W, eG-8R, and eY15H in patients 4, 5, and 6, respectively. Surface expressions of cP121Rand eP121T-AChR were 80% and 138% of the corresponding wild-type AChR, whereas eR20W, eG-8R, and eY15H reduced receptor expression to 27%, 35%, and 30% of wild-type eAChR, respectively. cV221Afs*44 and cY63* are null variants. Thus, cP121R and eP121T determine the phenotype. cP121R and eP121T shorten channel opening burst duration to 28% and 18% of corresponding wild-type AChR by reducing the channel gating equilibrium constant 44-and 63-fold, respectively. Interpretation: Similar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine-binding site of the AChR c and e subunits causes Escobar syndrome without pterygium and fast-channel CMS, respectively, suggesting that therapy for the fast-channel CMS will benefit Escobar syndrome.