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词条 SHANK3
释义

  1. Function

  2. Clinical significance

  3. Interactions

  4. Mouse models

  5. Rat Models

  6. References

  7. Further reading

  8. External links

{{Infobox_gene}}

SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a protein that in humans is encoded by the SHANK3 gene on chromosome 22.[1] Additional isoforms have been described for this gene but they have not yet been experimentally verified.

Function

This gene is a member of the Shank gene family. The gene encodes a protein that contains 5 interaction domains or motifs including the ankyrin repeats domain (ANK), a src 3 domain (SH3), a proline-rich domain, a PDZ domain and a SAM (sterile α motif) domain[2]. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.[3]

Clinical significance

Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome,[4] although not in all cases.[5]

Interactions

SHANK3 has been shown to interact with ARHGEF7.[6]

Mouse models

Mouse models of SHANK3 include N-terminal knock-outs[7][8] and a PDZ domain knock-out[9] all of which also show social interaction deficits and variable other phenotypes. Most of these mice are homozygous knock-outs whereas all the human Shank3 mutations have been heterozygous.

In an inducible knockout, restoration of Shank3 expression in adult mice promoted dendritic spine growth and recovered normal grooming behaviour and voluntary social interaction.[10] However, the reduced locomotion, anxiety and rotarod deficits remained. Germline restoration of the gene's expression rescued all measured phenotypes. Experiments on different developmental windows suggested that early intervention was more effective in restoring behavioural traits.

Rat Models

A rat model of SHANK3 was developed using zinc finger nucleases targeting exon 6 of the ankyrin (ANK) repeat domain. The deletion (-68bp) resulted in reduction of the full length SHANK3a protein. It is unclear if the expression of other isoforms (b and c) of SHANK3 is affected in this rodent model. The shank3 mutant rats have deficits in long-term social recognition memory but not short-term social recognition memory as well as deficits in attention. These mutant also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein.

References

1. ^{{cite web | title = Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85358| access-date = }}
2. ^{{cite journal | vauthors = Sheng M, Kim E | title = The Shank family of scaffold proteins | journal = Journal of Cell Science | volume = 113 ( Pt 11) | pages = 1851–6 | date = June 2000 | pmid = 10806096 }}
3. ^{{cite journal | vauthors = Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED | title = ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease | journal = Journal of Neurochemistry | volume = 81 | issue = 5 | pages = 903–10 | date = June 2002 | pmid = 12065602 | doi = 10.1046/j.1471-4159.2002.00931.x }}
4. ^{{cite journal | vauthors = Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS | title = Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome) | journal = Journal of Medical Genetics | volume = 48 | issue = 11 | pages = 761–6 | date = November 2011 | pmid = 21984749 | doi = 10.1136/jmedgenet-2011-100225 }}
5. ^{{cite journal | vauthors = Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K | title = A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 3 | pages = 806–9 | date = March 2014 | pmid = 24375995 | doi = 10.1002/ajmg.a.36358 }}
6. ^{{cite journal | vauthors = Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E | title = The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 21 | pages = 19220–9 | date = May 2003 | pmid = 12626503 | doi = 10.1074/jbc.M301052200 }}
7. ^{{cite journal | vauthors = Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH | title = Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3 | journal = Human Molecular Genetics | volume = 20 | issue = 15 | pages = 3093–108 | date = August 2011 | pmid = 21558424 | pmc = 3131048 | doi = 10.1093/hmg/ddr212 }}
8. ^{{cite journal | vauthors = Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD | title = Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication | journal = Molecular Autism | volume = 1 | issue = 1 | pages = 15 | date = December 2010 | pmid = 21167025 | pmc = 3019144 | doi = 10.1186/2040-2392-1-15 }}
9. ^{{cite journal | vauthors = Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G | title = Shank3 mutant mice display autistic-like behaviours and striatal dysfunction | journal = Nature | volume = 472 | issue = 7344 | pages = 437–42 | date = April 2011 | pmid = 21423165 | pmc = 3090611 | doi = 10.1038/nature09965 | url = http://dspace.mit.edu/bitstream/1721.1/87697/1/Feng_Shank3%20mutant.pdf }}
10. ^{{cite journal | vauthors = Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G | title = Adult restoration of Shank3 expression rescues selective autistic-like phenotypes | journal = Nature | volume = 530 | issue = 7591 | pages = 481–4 | date = February 2016 | pmid = 26886798 | doi = 10.1038/nature16971 | pmc = 4898763 }}

Further reading

{{refbegin | 2}}
  • {{cite journal | vauthors = Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE | title = SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients | journal = Nature | volume = 503 | issue = 7475 | pages = 267–71 | date = November 2013 | pmid = 24132240 | doi = 10.1038/nature12618 }}
  • {{cite journal | vauthors = Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF | title = Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins | journal = Neuron | volume = 23 | issue = 3 | pages = 583–92 | date = July 1999 | pmid = 10433269 | doi = 10.1016/S0896-6273(00)80810-7 }}
  • {{cite journal | vauthors = Sheng M, Kim E | title = The Shank family of scaffold proteins | journal = Journal of Cell Science | volume = 113 ( Pt 11) | issue = 11 | pages = 1851–6 | date = June 2000 | pmid = 10806096 | doi = }}
  • {{cite journal | vauthors = Boeckers TM, Kreutz MR, Winter C, Zuschratter W, Smalla KH, Sanmarti-Vila L, Wex H, Langnaese K, Bockmann J, Garner CC, Gundelfinger ED | title = Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density | journal = The Journal of Neuroscience | volume = 19 | issue = 15 | pages = 6506–18 | date = August 1999 | pmid = 10414979 | doi = }}
  • {{cite journal | vauthors = Hirosawa M, Nagase T, Murahashi Y, Kikuno R, Ohara O | title = Identification of novel transcribed sequences on human chromosome 22 by expressed sequence tag mapping | journal = DNA Research | volume = 8 | issue = 1 | pages = 1–9 | date = February 2001 | pmid = 11258795 | doi = 10.1093/dnares/8.1.1 }}
  • {{cite journal | vauthors = Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, Zuffardi O | title = Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome | journal = American Journal of Human Genetics | volume = 69 | issue = 2 | pages = 261–8 | date = August 2001 | pmid = 11431708 | pmc = 1235301 | doi = 10.1086/321293 }}
  • {{cite journal | vauthors = Soltau M, Richter D, Kreienkamp HJ | title = The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42 | journal = Molecular and Cellular Neurosciences | volume = 21 | issue = 4 | pages = 575–83 | date = December 2002 | pmid = 12504591 | doi = 10.1006/mcne.2002.1201 }}
  • {{cite journal | vauthors = Bonaglia MC, Giorda R, Mani E, Aceti G, Anderlid BM, Baroncini A, Pramparo T, Zuffardi O | title = Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome | journal = Journal of Medical Genetics | volume = 43 | issue = 10 | pages = 822–8 | date = October 2006 | pmid = 16284256 | pmc = 2563164 | doi = 10.1136/jmg.2005.038604 }}
  • {{cite journal | vauthors = Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T | title = Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders | journal = Nature Genetics | volume = 39 | issue = 1 | pages = 25–7 | date = January 2007 | pmid = 17173049 | pmc = 2082049 | doi = 10.1038/ng1933 }}
  • {{cite journal | vauthors = Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW | title = Contribution of SHANK3 mutations to autism spectrum disorder | journal = American Journal of Human Genetics | volume = 81 | issue = 6 | pages = 1289–97 | date = December 2007 | pmid = 17999366 | pmc = 2276348 | doi = 10.1086/522590 }}
  • {{cite journal | vauthors = Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G | title = Adult restoration of Shank3 expression rescues selective autistic-like phenotypes | journal = Nature | volume = 530 | issue = 7591 | pages = 481–4 | date = February 2016 | pmid = 26886798 | doi = 10.1038/nature16971 | pmc = 4898763 }}
{{refend}}

External links

  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gr_22q13_3 GeneReviews/NCBI/NIH/UW entry on Phelan-McDermid or 22q13.3 deletion syndrome]
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