“RAPSN”的意思、由来-开放百科全书

Function

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.^[2]

Role in health and disease

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.^[3]

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.^[4]

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^[5]

Interactions

References

1. ^{{cite journal | vauthors = Buckel A, Beeson D, James M, Vincent A | title = Cloning of cDNA encoding human rapsyn and mapping of the RAPSN gene locus to chromosome 11p11.2-p11.1 | journal = Genomics | volume = 35 | issue = 3 | pages = 613–6 | date = Aug 1996 | pmid = 8812503 | pmc = | doi = 10.1006/geno.1996.0409 }}
2. ^¹{{cite web | title = Entrez Gene: RAPSN receptor-associated protein of the synapse| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5913| accessdate = }}
3. ^{{cite journal | vauthors = Cossins J, Burke G, Maxwell S, Spearman H, Man S, Kuks J, Vincent A, Palace J, Fuhrer C, Beeson D | title = Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations | journal = Brain | volume = 129 | issue = Pt 10 | pages = 2773–83 | date = Oct 2006 | pmid = 16945936 | pmc = | doi = 10.1093/brain/awl219 }}
4. ^{{cite journal | vauthors = Cossins J, Burke G, Maxwell S, Spearman H, Man S, Kuks J, Vincent A, Palace J, Fuhrer C, Beeson D | title = Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations | journal = Brain | volume = 129 | issue = Pt 10 | pages = 2773–83 | date = Oct 2006 | pmid = 16945936 | pmc = | doi = 10.1093/brain/awl219 }}
5. ^{{cite journal | vauthors = Müller JS, Baumeister SK, Rasic VM, Krause S, Todorovic S, Kugler K, Müller-Felber W, Abicht A, Lochmüller H | title = Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations | journal = Neurology | volume = 67 | issue = 7 | pages = 1159–64 | date = Oct 2006 | pmid = 16931511 | pmc = | doi = 10.1212/01.wnl.0000233837.79459.40 }}
6. ^{{cite journal | vauthors = Fung ET, Lanahan A, Worley P, Huganir RL | title = Identification of a Torpedo homolog of Sam68 that interacts with the synapse organizing protein rapsyn | journal = FEBS Letters | volume = 437 | issue = 1–2 | pages = 29–33 | date = Oct 1998 | pmid = 9804166 | doi = 10.1016/S0014-5793(98)01151-X }}

Further reading

{{cite journal | vauthors = Apel ED, Roberds SL, Campbell KP, Merlie JP | title = Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex | journal = Neuron | volume = 15 | issue = 1 | pages = 115–26 | date = Jul 1995 | pmid = 7619516 | doi = 10.1016/0896-6273(95)90069-1 }}

{{cite journal | vauthors = Apel ED, Glass DJ, Moscoso LM, Yancopoulos GD, Sanes JR | title = Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold | journal = Neuron | volume = 18 | issue = 4 | pages = 623–35 | date = Apr 1997 | pmid = 9136771 | doi = 10.1016/S0896-6273(00)80303-7 }}

{{cite journal | vauthors = Yang SH, Armson PF, Cha J, Phillips WD | title = Clustering of GABAA receptors by rapsyn/43kD protein in vitro | journal = Molecular and Cellular Neurosciences | volume = 8 | issue = 6 | pages = 430–8 | year = 1997 | pmid = 9143560 | doi = 10.1006/mcne.1997.0597 }}

{{cite journal | vauthors = Ramarao MK, Cohen JB | title = Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 7 | pages = 4007–12 | date = Mar 1998 | pmid = 9520483 | pmc = 19953 | doi = 10.1073/pnas.95.7.4007 }}

{{cite journal | vauthors = Fung ET, Lanahan A, Worley P, Huganir RL | title = Identification of a Torpedo homolog of Sam68 that interacts with the synapse organizing protein rapsyn | journal = FEBS Letters | volume = 437 | issue = 1–2 | pages = 29–33 | date = Oct 1998 | pmid = 9804166 | doi = 10.1016/S0014-5793(98)01151-X }}

{{cite journal | vauthors = Qian X, Riccio A, Zhang Y, Ginty DD | title = Identification and characterization of novel substrates of Trk receptors in developing neurons | journal = Neuron | volume = 21 | issue = 5 | pages = 1017–29 | date = Nov 1998 | pmid = 9856458 | doi = 10.1016/S0896-6273(00)80620-0 }}

{{cite journal | vauthors = Zhou H, Glass DJ, Yancopoulos GD, Sanes JR | title = Distinct domains of MuSK mediate its abilities to induce and to associate with postsynaptic specializations | journal = The Journal of Cell Biology | volume = 146 | issue = 5 | pages = 1133–46 | date = Sep 1999 | pmid = 10477765 | pmc = 2169478 | doi = 10.1083/jcb.146.5.1133 }}

{{cite journal | vauthors = Han H, Noakes PG, Phillips WD | title = Overexpression of rapsyn inhibits agrin-induced acetylcholine receptor clustering in muscle cells | journal = Journal of Neurocytology | volume = 28 | issue = 9 | pages = 763–75 | date = Sep 1999 | pmid = 10859577 | doi = 10.1023/A:1007098406748 }}

{{cite journal | vauthors = Ramarao MK, Bianchetta MJ, Lanken J, Cohen JB | title = Role of rapsyn tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering | journal = The Journal of Biological Chemistry | volume = 276 | issue = 10 | pages = 7475–83 | date = Mar 2001 | pmid = 11087759 | doi = 10.1074/jbc.M009888200 }}

{{cite journal | vauthors = Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF | title = Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse | journal = Nature | volume = 410 | issue = 6832 | pages = 1057–64 | date = Apr 2001 | pmid = 11323662 | doi = 10.1038/35074025 }}

{{cite journal | vauthors = Bartoli M, Ramarao MK, Cohen JB | title = Interactions of the rapsyn RING-H2 domain with dystroglycan | journal = The Journal of Biological Chemistry | volume = 276 | issue = 27 | pages = 24911–7 | date = Jul 2001 | pmid = 11342559 | doi = 10.1074/jbc.M103258200 }}

{{cite journal | vauthors = Ohno K, Engel AG, Shen XM, Selcen D, Brengman J, Harper CM, Tsujino A, Milone M | title = Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome | journal = American Journal of Human Genetics | volume = 70 | issue = 4 | pages = 875–85 | date = Apr 2002 | pmid = 11791205 | pmc = 379116 | doi = 10.1086/339465 }}

{{cite journal | vauthors = Marchand S, Devillers-Thiéry A, Pons S, Changeux JP, Cartaud J | title = Rapsyn escorts the nicotinic acetylcholine receptor along the exocytic pathway via association with lipid rafts | journal = The Journal of Neuroscience | volume = 22 | issue = 20 | pages = 8891–901 | date = Oct 2002 | pmid = 12388596 | doi = 10.1523/JNEUROSCI.22-20-08891.2002}}

{{cite journal | vauthors = Huebsch KA, Maimone MM | title = Rapsyn-mediated clustering of acetylcholine receptor subunits requires the major cytoplasmic loop of the receptor subunits | journal = Journal of Neurobiology | volume = 54 | issue = 3 | pages = 486–501 | date = Feb 2003 | pmid = 12532399 | doi = 10.1002/neu.10177 }}

{{cite journal | vauthors = Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG | title = E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome | journal = Human Molecular Genetics | volume = 12 | issue = 7 | pages = 739–48 | date = Apr 2003 | pmid = 12651869 | doi = 10.1093/hmg/ddg089 }}

{{cite journal | vauthors = Dunne V, Maselli RA | title = Identification of pathogenic mutations in the human rapsyn gene | journal = Journal of Human Genetics | volume = 48 | issue = 4 | pages = 204–7 | year = 2003 | pmid = 12730725 | doi = 10.1007/s10038-003-0005-7 }}

{{cite journal | vauthors = Müller JS, Mildner G, Müller-Felber W, Schara U, Krampfl K, Petersen B, Petrova S, Stucka R, Mortier W, Bufler J, Kurlemann G, Huebner A, Merlini L, Lochmüller H, Abicht A | title = Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients | journal = Neurology | volume = 60 | issue = 11 | pages = 1805–10 | date = Jun 2003 | pmid = 12796535 | doi = 10.1212/01.wnl.0000072262.14931.80 }}

{{cite journal | vauthors = Richard P, Gaudon K, Andreux F, Yasaki E, Prioleau C, Bauché S, Barois A, Ioos C, Mayer M, Routon MC, Mokhtari M, Leroy JP, Fournier E, Hainque B, Koenig J, Fardeau M, Eymard B, Hantaï D | title = Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes | journal = Journal of Medical Genetics | volume = 40 | issue = 6 | pages = 81e–81 | date = Jun 2003 | pmid = 12807980 | pmc = 1735489 | doi = 10.1136/jmg.40.6.e81 }}