CHRNE
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Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.[3][4]
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 achetylcholine 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.[4]
Role in health and disease
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.[5]
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.[6] 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.[7]
See also
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ 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. PMID 7688301.
- 1 2 "Entrez Gene: CHRNE cholinergic receptor, nicotinic, epsilon".
- ↑ Cossins, J.; Burke, G.; Maxwell, S.; Spearman, H.; Man, S.; Kuks, J.; Vincent, A.; Palace, J.; Fuhrer, C.; Beeson, D. (2006). "Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations". Brain. 129 (10): 2773–2783. doi:10.1093/brain/awl219. PMID 16945936.
- ↑ 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, J. S.; 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. PMID 22678886.
- ↑ Shen, X. -M.; Brengman, J. M.; Edvardson, S.; Sine, S. M.; Engel, A. G. (2012). "Highly fatal fast-channel syndrome caused by AChR subunit mutation at the agonist binding site". Neurology. 79 (5): 449–454. doi:10.1212/WNL.0b013e31825b5bda. PMC 3405251
. PMID 22592360.
Further reading
- Hantaï D, Richard P, Koenig J, Eymard B (2005). "Congenital myasthenic syndromes". Curr. Opin. Neurol. 17 (5): 539–51. doi:10.1097/00019052-200410000-00004. PMID 15367858.
- Yu XM, Hall ZW (1991). "Extracellular domains mediating epsilon subunit interactions of muscle acetylcholine receptor". Nature. 352 (6330): 64–7. doi:10.1038/352064a0. PMID 1712080.
- Ohno K, Hutchinson DO, Milone M, et al. (1995). "Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit". Proc. Natl. Acad. Sci. U.S.A. 92 (3): 758–62. doi:10.1073/pnas.92.3.758. PMC 42699. PMID 7531341.
- 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. PMID 7538206.
- 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. PMID 7902325.
- 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. PMID 7958418.
- 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. PMID 8232384.
- Ohno K, Wang HL, Milone M, et al. (1996). "Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit". Neuron. 17 (1): 157–70. doi:10.1016/S0896-6273(00)80289-5. PMID 8755487.
- Engel AG, Ohno K, Milone M, et al. (1997). "New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome". Hum. Mol. Genet. 5 (9): 1217–27. doi:10.1093/hmg/5.9.1217. PMID 8872460.
- Engel AG, Ohno K, Bouzat C, et al. (1997). "End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit". Ann. Neurol. 40 (5): 810–7. doi:10.1002/ana.410400521. PMID 8957026.
- Ohno K, Quiram PA, Milone M, et al. (1997). "Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations". Hum. Mol. Genet. 6 (5): 753–66. doi:10.1093/hmg/6.5.753. PMID 9158150.
- Nichols P, Croxen R, Vincent A, et al. (1999). "Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome". Ann. Neurol. 45 (4): 439–43. doi:10.1002/1531-8249(199904)45:4<439::AID-ANA4>3.0.CO;2-W. PMID 10211467.
- Croxen R, Newland C, Betty M, et al. (1999). "Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome". Ann. Neurol. 46 (4): 639–47. doi:10.1002/1531-8249(199910)46:4<639::AID-ANA13>3.0.CO;2-1. PMID 10514102.
- 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. PMID 10534268.
- Kindler CH, Verotta D, Gray AT, et al. (2000). "Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium". Anesthesiology. 92 (3): 821–32. doi:10.1097/00000542-200003000-00026. PMID 10719961.
- Wang HL, Ohno K, Milone M, et al. (2000). "Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome". J. Gen. Physiol. 116 (3): 449–62. doi:10.1085/jgp.116.3.449. PMC 2233692. PMID 10962020.
- Sieb JP, Kraner S, Rauch M, Steinlein OK (2000). "Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations". Hum. Genet. 107 (2): 160–4. doi:10.1007/s004390000359. PMID 11030414.
- Dan I, Watanabe NM, Kajikawa E, et al. (2002). "Overlapping of MINK and CHRNE gene loci in the course of mammalian evolution". Nucleic Acids Res. 30 (13): 2906–10. doi:10.1093/nar/gkf407. PMC 117062. PMID 12087176.
- Croxen R, Hatton C, Shelley C, et al. (2002). "Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes". Neurology. 59 (2): 162–8. doi:10.1212/wnl.59.2.162. PMID 12141316. (Retracted. If this is intentional, please replace
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External links
- CHRNE protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.