Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNEgene.[5][6]
Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome.[6]
Congenital myasthenic syndrome (CMS) is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). The majority of mutations causing CMS are found in the AChR subunits genes.[7]
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult AChR subunits. Mutations of the AChR often result in endplate deficiency. The most common AChR gene mutation that underlies CMS is the mutation of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR.[8] One type of mutation of the epsilon subunit of the AChR introduces an arginine (Arg) into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.[9]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Beeson D, Brydson M, Betty M, Jeremiah S, Povey S, Vincent A, Newsom-Davis J (Sep 1993). "Primary structure of the human muscle acetylcholine receptor. cDNA cloning of the gamma and epsilon subunits". Eur J Biochem. 215 (2): 229–38. doi:10.1111/j.1432-1033.1993.tb18027.x. PMID7688301.
^Abicht A, Dusl M, Gallenmüller C, Guergueltcheva V, Schara U, Della Marina A, Wibbeler E, Almaras S, Mihaylova V, Von Der Hagen M, Huebner A, Chaouch A, Müller JS, Lochmüller H (2012). "Congenital myasthenic syndromes: Achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: A study of 680 patients". Human Mutation. 33 (10): 1474–1484. doi:10.1002/humu.22130. PMID22678886. S2CID30868022.
Gomez CM, Gammack JT (1995). "A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome". Neurology. 45 (5): 982–5. doi:10.1212/wnl.45.5.982. PMID7538206. S2CID35877992.
Lobos EA (1993). "Five subunit genes of the human muscle nicotinic acetylcholine receptor are mapped to two linkage groups on chromosomes 2 and 17". Genomics. 17 (3): 642–50. doi:10.1006/geno.1993.1384. PMID7902325.
Brenner HR, Rotzler S, Kues WA, et al. (1994). "Nerve-dependent induction of AChR epsilon-subunit gene expression in muscle is independent of state of differentiation". Dev. Biol. 165 (2): 527–36. doi:10.1006/dbio.1994.1272. PMID7958418.
Uchitel O, Engel AG, Walls TJ, et al. (1993). "Congenital myasthenic syndromes: II. Syndrome attributed to abnormal interaction of acetylcholine with its receptor". Muscle Nerve. 16 (12): 1293–301. doi:10.1002/mus.880161205. PMID8232384. S2CID26474245.
Abicht A, Stucka R, Karcagi V, et al. (1999). "A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin". Neurology. 53 (7): 1564–9. doi:10.1212/wnl.53.7.1564. PMID10534268.
