SHANK3

SHANK3
Identifikatori
Aliasi	SHANK3
Vanjski ID-jevi	OMIM: 606230 MGI: 1930016 HomoloGene: 75163 GeneCards: SHANK3
Lokacija gena (čovjek)
Hrom.	Hromosom 22 (čovjek)
Kraj	50,733,212 bp
Lokacija gena (miš)
Hrom.	Hromosom 15 (miš)
Kraj	89,444,464 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• SH3 domain binding; • scaffold protein binding; • vezivanje iona cinka; • protein C-terminus binding; • GO:0001948, GO:0016582 vezivanje za proteine; • synaptic receptor adaptor activity; • actin binding; • ionotropic glutamate receptor binding; • protein self-association; • signaling receptor complex adaptor activity;
Ćelijska komponenta	• citoplazma; • postsynaptic membrane; • projekcija ćelije; • membrana; • ćelijska membrana; • dendritična kičma; • sinapsa; • međućelijske veze; • ciliary membrane; • neuron spine; • neuron projection; • GO:0097483, GO:0097481 postsynaptic density; • citosol; • extrinsic component of cytoplasmic side of plasma membrane; • ionotropic glutamate receptor complex; • dendrit;
Biološki proces	• positive regulation of long-term synaptic potentiation; • positive regulation of synapse structural plasticity; • NMDA glutamate receptor clustering; • regulation of long-term synaptic depression; • positive regulation of glutamate receptor signaling pathway; • postsynaptic density assembly; • negative regulation of actin filament bundle assembly; • negative regulation of cell volume; • positive regulation of AMPA receptor activity; • Memorija; • Učenje; • positive regulation of dendritic spine development; • MAPK cascade; • striatal medium spiny neuron differentiation; • AMPA glutamate receptor clustering; • dendritic spine morphogenesis; • vocal learning; • vocalization behavior; • adult behavior; • positive regulation of synaptic transmission, glutamatergic; • positive regulation of long-term neuronal synaptic plasticity; • regulation of long-term synaptic potentiation; • positive regulation of excitatory postsynaptic potential; • socijalno ponašanje; • guanylate kinase-associated protein clustering; • synapse assembly; • regulation of dendritic spine morphogenesis; • brain morphogenesis; • axon guidance; • synaptic assembly at neuromuscular junction; • long-term potentiation; • regulation of AMPA receptor activity;
	Izvori:Amigo / QuickGO
Ortolozi
	85358
	58234
	ENSG00000251322
	ENSMUSG00000022623
	Q9BYB0
	Q4ACU6
	NM_001080420; NM_001372044
	NM_021423
	NP_277052
	NP_067398
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

SH3 i multiplo ponavljajući ankirinski domeni 3 (Shank3), znani i kao prolinom bogati sinapsno vezani protein 2 (ProSAP2), jest protein koji je kod ljudi kodiran genom SHANK3 sa hromosoma 22.^[5] Za ovaj gen opisane su i dodatne izoforme, ali još uvijek nisu eksperimentalno potvrđene.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 1.731 aminokiselina, a molekulska težina 184.667 Da.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MDGPGASAVV	VRVGIPDLQQ	TKCLRLDPAA	PVWAAKQRVL	CALNHSLQDA
LNYGLFQPPS	RGRAGKFLDE	ERLLQEYPPN	LDTPLPYLEF	RYKRRVYAQN
LIDDKQFAKL	HTKANLKKFM	DYVQLHSTDK	VARLLDKGLD	PNFHDPDSGE
CPLSLAAQLD	NATDLLKVLK	NGGAHLDFRT	RDGLTAVHCA	TRQRNAAALT
TLLDLGASPD	YKDSRGLTPL	YHSALGGGDA	LCCELLLHDH	AQLGITDENG
WQEIHQACRF	GHVQHLEHLL	FYGADMGAQN	ASGNTALHIC	ALYNQESCAR
VLLFRGANRD	VRNYNSQTAF	QVAIIAGNFE	LAEVIKTHKD	SDVVPFRETP
SYAKRRRLAG	PSGLASPRPL	QRSASDINLK	GEAQPAASPG	PSLRSLPHQL
LLQRLQEEKD	RDRDADQESN	ISGPLAGRAG	QSKISPSGPG	GPGPAPGPGP
APPAPPAPPP	RGPKRKLYSA	VPGRKFIAVK	AHSPQGEGEI	PLHRGEAVKV
LSIGEGGFWE	GTVKGRTGWF	PADCVEEVQM	RQHDTRPETR	EDRTKRLFRH
YTVGSYDSLT	SHSDYVIDDK	VAVLQKRDHE	GFGFVLRGAK	AETPIEEFTP
TPAFPALQYL	ESVDVEGVAW	RAGLRTGDFL	IEVNGVNVVK	VGHKQVVALI
RQGGNRLVMK	VVSVTRKPEE	DGARRRAPPP	PKRAPSTTLT	LRSKSMTAEL
EELASIRRRK	GEKLDEMLAA	AAEPTLRPDI	ADADSRAATV	KQRPTSRRIT
PAEISSLFER	QGLPGPEKLP	GSLRKGIPRT	KSVGEDEKLA	SLLEGRFPRS
TSMQDPVREG	RGIPPPPQTA	PPPPPAPYYF	DSGPPPAFSP	PPPPGRAYDT
VRSSFKPGLE	ARLGAGAAGL	YEPGAALGPL	PYPERQKRAR	SMIILQDSAP
ESGDAPRPPP	AATPPERPKR	RPRPPGPDSP	YANLGAFSAS	LFAPSKPQRR
KSPLVKQLQV	EDAQERAALA	VGSPGPGGGS	FAREPSPTHR	GPRPGGLDYG
AGDGPGLAFG	GPGPAKDRRL	EERRRSTVFL	SVGAIEGSAP	GADLPSLQPS
RSIDERLLGT	GPTAGRDLLL	PSPVSALKPL	VSGPSLGPSG	STFIHPLTGK
PLDPSSPLAL	ALAARERALA	SQAPSRSPTP	VHSPDADRPG	PLFVDVQARD
PERGSLASPA	FSPRSPAWIP	VPARREAEKV	PREERKSPED	KKSMILSVLD
TSLQRPAGLI	VVHATSNGQE	PSRLGGAEEE	RPGTPELAPA	PMQSAAVAEP
LPSPRAQPPG	GTPADAGPGQ	GSSEEEPELV	FAVNLPPAQL	SSSDEETREE
LARIGLVPPP	EEFANGVLLA	TPLAGPGPSP	TTVPSPASGK	PSSEPPPAPE
SAADSGVEEA	DTRSSSDPHL	ETTSTISTVS	SMSTLSSESG	ELTDTHTSFA
DGHTFLLEKP	PVPPKPKLKS	PLGKGPVTFR	DPLLKQSSDS	ELMAQQHHAA
SAGLASAAGP	ARPRYLFQRR	SKLWGDPVES	RGLPGPEDDK	PTVISELSSR
LQQLNKDTRS	LGEEPVGGLG	SLLDPAKKSP	IAAARLFSSL	GELSSISAQR
SPGGPGGGAS	YSVRPSGRYP	VARRAPSPVK	PASLERVEGL	GAGAGGAGRP
FGLTPPTILK	SSSLSIPHEP	KEVRFVVRSV	SARSRSPSPS	PLPSPASGPG
PGAPGPRRPF	QQKPLQLWSK	FDVGDWLESI	HLGEHRDRFE	DHEIEGAHLP
ALTKDDFVEL	GVTRVGHRMN	IERALRQLDG	S

Funkcija

Ovaj gen je član porodice Shank gena. Kodira protein koji sadrži pet interakcijskih domena ili motiva uključujući domen ankirinskog ponavljanja (ANK), src 3 domen (SH3), domen bogat prolinom i PDZ domen i sterilni α motiv (SAM).^[6] Shank proteini su proteini multidomenski skele postsinapsne gustine koji povezuju neurotransmiterske receptore, ionske kanale i druge membranske proteine sa aktinskim citoskeletom i signalnim putevima vezanim za G-protein. Također imaju ulogu u formiranju sinapse i sazrijevanju dendritske kičme.^[7]

Klinički značaj

Mutacije u ovom genu povezane su sa poremećajima iz spektra autizma.^[8] Ovaj gen često nedostaje kod pacijenata sa sindromom delecije 22q13.3 (Phelan-McDermid sindrom),^[9] iako ne u svim slučajevima.^[10]

Interakcije

Pokazano je da SHANK3 reaguje sa ARHGEF7.^[11]

Mišji modeli

Modeli mišjeg SHANK3 uključuju N-terminalne nokaute^[12]^[13] and a PDZ domain knock-out^[14] svi oni također pokazuju deficite socijalne interakcije i druge varijabilne fenotipove. Većina ovih miševa su homozigotni nokauti, dok su sve ljudske mutacije gena Shank3 bile heterozigotne.

U inducibilnom nokautu, obnavljanje ekspresije Shank3 kod odraslih miševa potaknulo je dendritski rast kičme i povratilo normalno ponašanje u njezi i dobrovoljnu društvenu interakciju.^[15] Međutim, ostali su deficiti smanjena lokomocija, anksioznost i rotarod. Obnavljanje ekspresije gena zametne linije spasilo je sve izmjerene fenotipove. Eksperimenti na različitim razvojnim prozorima sugerirali su da je rana intervencija učinkovitija u obnavljanju osobina ponašanja.

Pacovski modeli

Pacovski model SHANK3 je razvijen korištenjem nukleaza cinkovog prsta ciljanog na egzon 6 domena ankirinskog ponavljanja (ANK). Delecija (–68bp) rezultirala je smanjenjem pune dužine proteina SHANK3a. Nije jasno da li je ekspresija drugih izoformi (b i c) SHANK3 pogođena u ovom modelu glodara. Mutantni pacovi shank3 imaju deficite u dugotrajnoj memoriji, ali ne i kratkoročnoj memoriji društvenog prepoznavanja, kao i deficitu pažnje. Ovi mutanti također imaju oštećenu sinapsnu plastičnost. Kod ljudi opisano je pet pacijenata koji imaju različite mutacije u egzonu 6 proteina SHANK3.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000251322 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000022623 - Ensembl, maj 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.
^ ^a ^b "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3".
^ Sheng M, Kim E (juni 2000). "The Shank family of scaffold proteins". Journal of Cell Science. 113 ( Pt 11) (11): 1851–6. doi:10.1242/jcs.113.11.1851. PMID 10806096.
^ Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED (juni 2002). "ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease". Journal of Neurochemistry. 81 (5): 903–10. doi:10.1046/j.1471-4159.2002.00931.x. PMID 12065602. S2CID 19894590.
^ Brown, EA; et al. (2018). "Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models". Molecular Autism. BioMed Central. 9 (48): 1-16. doi:10.1186/s13229-018-0229-1. PMC 6139139. PMID 30237867. Arhivirano s originala, 29. 3. 2021. Pristupljeno 19. 11. 2021.
^ Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS (novembar 2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)". Journal of Medical Genetics. 48 (11): 761–6. doi:10.1136/jmedgenet-2011-100225. PMID 21984749. S2CID 28620399.
^ Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K (mart 2014). "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". American Journal of Medical Genetics. Part A. 164A (3): 806–9. doi:10.1002/ajmg.a.36358. PMID 24375995. S2CID 7917552.
^ Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E (maj 2003). "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". The Journal of Biological Chemistry. 278 (21): 19220–9. doi:10.1074/jbc.M301052200. PMID 12626503.
^ 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 (august 2011). "Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3". Human Molecular Genetics. 20 (15): 3093–108. doi:10.1093/hmg/ddr212. PMC 3131048. PMID 21558424.
^ 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 (decembar 2010). "Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication". Molecular Autism. 1 (1): 15. doi:10.1186/2040-2392-1-15. PMC 3019144. PMID 21167025.
^ Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (april 2011). "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction" (PDF). Nature. 472 (7344): 437–42. Bibcode:2011Natur.472..437P. doi:10.1038/nature09965. PMC 3090611. PMID 21423165.
^ Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G (februar 2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature. 530 (7591): 481–4. Bibcode:2016Natur.530..481M. doi:10.1038/nature16971. PMC 4898763. PMID 26886798.

Dopunska literatura

Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE (novembar 2013). "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients". Nature. 503 (7475): 267–71. Bibcode:2013Natur.503..267S. doi:10.1038/nature12618. PMC 5559273. PMID 24132240.
Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (juli 1999). "Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins". Neuron. 23 (3): 583–92. doi:10.1016/S0896-6273(00)80810-7. PMID 10433269.
Sheng M, Kim E (juni 2000). "The Shank family of scaffold proteins". Journal of Cell Science. 113 ( Pt 11) (11): 1851–6. doi:10.1242/jcs.113.11.1851. PMID 10806096.
Boeckers TM, Kreutz MR, Winter C, Zuschratter W, Smalla KH, Sanmarti-Vila L, Wex H, Langnaese K, Bockmann J, Garner CC, Gundelfinger ED (august 1999). "Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density". The Journal of Neuroscience. 19 (15): 6506–18. doi:10.1523/JNEUROSCI.19-15-06506.1999. PMC 6782800. PMID 10414979.
Hirosawa M, Nagase T, Murahashi Y, Kikuno R, Ohara O (februar 2001). "Identification of novel transcribed sequences on human chromosome 22 by expressed sequence tag mapping". DNA Research. 8 (1): 1–9. doi:10.1093/dnares/8.1.1. PMID 11258795.
Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, Zuffardi O (august 2001). "Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome". American Journal of Human Genetics. 69 (2): 261–8. doi:10.1086/321293. PMC 1235301. PMID 11431708.
Soltau M, Richter D, Kreienkamp HJ (decembar 2002). "The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42". Molecular and Cellular Neurosciences. 21 (4): 575–83. doi:10.1006/mcne.2002.1201. PMID 12504591. S2CID 572407.
Bonaglia MC, Giorda R, Mani E, Aceti G, Anderlid BM, Baroncini A, Pramparo T, Zuffardi O (oktobar 2006). "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". Journal of Medical Genetics. 43 (10): 822–8. doi:10.1136/jmg.2005.038604. PMC 2563164. PMID 16284256.
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 (januar 2007). "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nature Genetics. 39 (1): 25–7. doi:10.1038/ng1933. PMC 2082049. PMID 17173049.
Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (decembar 2007). "Contribution of SHANK3 mutations to autism spectrum disorder". American Journal of Human Genetics. 81 (6): 1289–97. doi:10.1086/522590. PMC 2276348. PMID 17999366.
Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G (februar 2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature. 530 (7591): 481–4. Bibcode:2016Natur.530..481M. doi:10.1038/nature16971. PMC 4898763. PMID 26886798.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Phelan-McDermid or 22q13.3 deletion syndrome

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000251322 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000022623 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3".

[6] Sheng M, Kim E (juni 2000). "The Shank family of scaffold proteins". Journal of Cell Science. 113 ( Pt 11) (11): 1851–6. doi:10.1242/jcs.113.11.1851. PMID 10806096.

[7] Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED (juni 2002). "ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease". Journal of Neurochemistry. 81 (5): 903–10. doi:10.1046/j.1471-4159.2002.00931.x. PMID 12065602. S2CID 19894590.

[8] Brown, EA; et al. (2018). "Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models". Molecular Autism. BioMed Central. 9 (48): 1-16. doi:10.1186/s13229-018-0229-1. PMC 6139139. PMID 30237867. Arhivirano s originala, 29. 3. 2021. Pristupljeno 19. 11. 2021.

[9] Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS (novembar 2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)". Journal of Medical Genetics. 48 (11): 761–6. doi:10.1136/jmedgenet-2011-100225. PMID 21984749. S2CID 28620399.

[10] Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K (mart 2014). "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". American Journal of Medical Genetics. Part A. 164A (3): 806–9. doi:10.1002/ajmg.a.36358. PMID 24375995. S2CID 7917552.

[pmid12626503-11] Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E (maj 2003). "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". The Journal of Biological Chemistry. 278 (21): 19220–9. doi:10.1074/jbc.M301052200. PMID 12626503.

[pmid21558424-12] 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 (august 2011). "Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3". Human Molecular Genetics. 20 (15): 3093–108. doi:10.1093/hmg/ddr212. PMC 3131048. PMID 21558424.

[pmid21167025-13] 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 (decembar 2010). "Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication". Molecular Autism. 1 (1): 15. doi:10.1186/2040-2392-1-15. PMC 3019144. PMID 21167025.

[pmid21423165-14] Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (april 2011). "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction" (PDF). Nature. 472 (7344): 437–42. Bibcode:2011Natur.472..437P. doi:10.1038/nature09965. PMC 3090611. PMID 21423165.

[pmid_26886798-15] Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G (februar 2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature. 530 (7591): 481–4. Bibcode:2016Natur.530..481M. doi:10.1038/nature16971. PMC 4898763. PMID 26886798.

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