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RAPSN
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| RAPSN | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | RAPSN, RAPSYN, RNF205, CMS11, CMS4C, FADS, receptor associated protein of the synapse, FADS2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601592; MGI: 99422; HomoloGene: 3708; GeneCards: RAPSN; OMA:RAPSN - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.[5][6]
Function
[edit]This protein belongs to a family of proteins that are receptor associated proteins of the synapse. It contains a conserved cAMP-dependent protein kinase phosphorylation site. It is believed to play some role in anchoring or stabilizing the nicotinic acetylcholine receptor at synaptic sites. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Two splice variants have been identified for this gene.[6]
Role in health and disease
[edit]In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of the acetylcholine receptor (AChR) on the postsynaptic folds. This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK protein), AChRs and the AChR-clustering protein rapsyn, encoded by RAPSN. Genetic mutations of the proteins in the neuromuscular junction are associated with Congenital myasthenic syndrome (CMS). Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor. The vast majority of mutations causing CMS are found in the AChR subunits and rapsyn genes.[7]
The rapsyn protein interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created as the folds do not form properly. Patients with CMS-related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease.[7]
Studies have shown that most patients with CMS that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene on both of their alleles. Two novel missense mutations that have been found are R164C and L283P and the result is a decrease in co-clustering of AChR with raspyn. A third mutation is the intronic base alteration IVS1-15C>A and it causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for CMS mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations[8] Interestingly, patients who bear the burden of CMS due to these rapsyn mutations often demonstrate a remarkable response to anticholinesterase drugs like pyridostigmine. Moreover, the supplemental inclusion of 3,4 DAP, ephedrine, or albuterol often yields significant clinical improvement.[9]
Interactions
[edit]References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000165917 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000002104 – Ensembl, May 2017
- ^ "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.
- ^ Buckel A, Beeson D, James M, Vincent A (August 1996). "Cloning of cDNA encoding human rapsyn and mapping of the RAPSN gene locus to chromosome 11p11.2-p11.1". Genomics. 35 (3): 613–616. doi:10.1006/geno.1996.0409. PMID 8812503.
- ^ a b "Entrez Gene: RAPSN receptor-associated protein of the synapse".
- ^ a b Cossins J, Burke G, Maxwell S, Spearman H, Man S, Kuks J, et al. (October 2006). "Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations". Brain. 129 (Pt 10): 2773–2783. doi:10.1093/brain/awl219. PMID 16945936.
- ^ Müller JS, Baumeister SK, Rasic VM, Krause S, Todorovic S, Kugler K, et al. (October 2006). "Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations". Neurology. 67 (7): 1159–1164. doi:10.1212/01.wnl.0000233837.79459.40. PMID 16931511. S2CID 41593780.
- ^ Liao X, Wang Y, Lai X, Wang S (February 2023). "The role of Rapsyn in neuromuscular junction and congenital myasthenic syndrome". Biomolecules and Biomedicine. 23 (5): 772–784. doi:10.17305/bb.2022.8641. PMC 10494853. PMID 36815443. S2CID 257100080.
- ^ Fung ET, Lanahan A, Worley P, Huganir RL (October 1998). "Identification of a Torpedo homolog of Sam68 that interacts with the synapse organizing protein rapsyn". FEBS Letters. 437 (1–2): 29–33. Bibcode:1998FEBSL.437...29F. doi:10.1016/S0014-5793(98)01151-X. PMID 9804166. S2CID 7842971.
Further reading
[edit]- Apel ED, Roberds SL, Campbell KP, Merlie JP (July 1995). "Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex". Neuron. 15 (1): 115–126. doi:10.1016/0896-6273(95)90069-1. PMID 7619516. S2CID 589282.
- Apel ED, Glass DJ, Moscoso LM, Yancopoulos GD, Sanes JR (April 1997). "Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold". Neuron. 18 (4): 623–635. doi:10.1016/S0896-6273(00)80303-7. PMID 9136771. S2CID 18020725.
- Yang SH, Armson PF, Cha J, Phillips WD (1997). "Clustering of GABAA receptors by rapsyn/43kD protein in vitro". Molecular and Cellular Neurosciences. 8 (6): 430–438. doi:10.1006/mcne.1997.0597. PMID 9143560. S2CID 140208903.
- Ramarao MK, Cohen JB (March 1998). "Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn". Proceedings of the National Academy of Sciences of the United States of America. 95 (7): 4007–4012. Bibcode:1998PNAS...95.4007R. doi:10.1073/pnas.95.7.4007. PMC 19953. PMID 9520483.
- Fung ET, Lanahan A, Worley P, Huganir RL (October 1998). "Identification of a Torpedo homolog of Sam68 that interacts with the synapse organizing protein rapsyn". FEBS Letters. 437 (1–2): 29–33. Bibcode:1998FEBSL.437...29F. doi:10.1016/S0014-5793(98)01151-X. PMID 9804166. S2CID 7842971.
- Qian X, Riccio A, Zhang Y, Ginty DD (November 1998). "Identification and characterization of novel substrates of Trk receptors in developing neurons". Neuron. 21 (5): 1017–1029. doi:10.1016/S0896-6273(00)80620-0. PMID 9856458. S2CID 12354383.
- Zhou H, Glass DJ, Yancopoulos GD, Sanes JR (September 1999). "Distinct domains of MuSK mediate its abilities to induce and to associate with postsynaptic specializations". The Journal of Cell Biology. 146 (5): 1133–1146. doi:10.1083/jcb.146.5.1133. PMC 2169478. PMID 10477765.
- Han H, Noakes PG, Phillips WD (September 1999). "Overexpression of rapsyn inhibits agrin-induced acetylcholine receptor clustering in muscle cells". Journal of Neurocytology. 28 (9): 763–775. doi:10.1023/A:1007098406748. PMID 10859577. S2CID 36518335.
- Ramarao MK, Bianchetta MJ, Lanken J, Cohen JB (March 2001). "Role of rapsyn tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering". The Journal of Biological Chemistry. 276 (10): 7475–7483. doi:10.1074/jbc.M009888200. PMID 11087759.
- Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF (April 2001). "Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse". Nature. 410 (6832): 1057–1064. Bibcode:2001Natur.410.1057L. doi:10.1038/35074025. PMID 11323662. S2CID 4372222.
- Bartoli M, Ramarao MK, Cohen JB (July 2001). "Interactions of the rapsyn RING-H2 domain with dystroglycan". The Journal of Biological Chemistry. 276 (27): 24911–24917. doi:10.1074/jbc.M103258200. PMID 11342559.
- Ohno K, Engel AG, Shen XM, Selcen D, Brengman J, Harper CM, et al. (April 2002). "Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome". American Journal of Human Genetics. 70 (4): 875–885. doi:10.1086/339465. PMC 379116. PMID 11791205.
- Marchand S, Devillers-Thiéry A, Pons S, Changeux JP, Cartaud J (October 2002). "Rapsyn escorts the nicotinic acetylcholine receptor along the exocytic pathway via association with lipid rafts". The Journal of Neuroscience. 22 (20): 8891–8901. doi:10.1523/JNEUROSCI.22-20-08891.2002. PMC 6757681. PMID 12388596.
- Huebsch KA, Maimone MM (February 2003). "Rapsyn-mediated clustering of acetylcholine receptor subunits requires the major cytoplasmic loop of the receptor subunits". Journal of Neurobiology. 54 (3): 486–501. doi:10.1002/neu.10177. PMID 12532399.
- Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG (April 2003). "E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome". Human Molecular Genetics. 12 (7): 739–748. doi:10.1093/hmg/ddg089. PMID 12651869.
- Dunne V, Maselli RA (2003). "Identification of pathogenic mutations in the human rapsyn gene". Journal of Human Genetics. 48 (4): 204–207. doi:10.1007/s10038-003-0005-7. PMID 12730725.
- Müller JS, Mildner G, Müller-Felber W, Schara U, Krampfl K, Petersen B, et al. (June 2003). "Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients". Neurology. 60 (11): 1805–1810. doi:10.1212/01.wnl.0000072262.14931.80. PMID 12796535. S2CID 30030861.
- Richard P, Gaudon K, Andreux F, Yasaki E, Prioleau C, Bauché S, et al. (June 2003). "Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes". Journal of Medical Genetics. 40 (6): 81e–81. doi:10.1136/jmg.40.6.e81. PMC 1735489. PMID 12807980.