SHANK3

SH3 and multiple ankyrin repeat domains 3
PDB rendering based on 2f3n.
Identifiers
Symbols	SHANK3 ; DEL22q13.3; PROSAP2; PSAP2; SCZD15; SPANK-2
External IDs	OMIM: 606230 MGI: 1930016 HomoloGene: 75163 GeneCards: SHANK3 Gene
Gene ontology Molecular function • actin binding • protein binding • protein C-terminus binding • zinc ion binding • SH3 domain binding • GKAP/Homer scaffold activity • ionotropic glutamate receptor binding • identical protein binding • scaffold protein binding Cellular component • cytoplasm • plasma membrane • cell junction • neuron projection • dendritic spine • neuron spine • postsynaptic membrane • ciliary membrane • neuronal postsynaptic density Biological process • MAPK cascade • synapse assembly • learning • memory • striatal medium spiny neuron differentiation • adult behavior • negative regulation of actin filament bundle assembly • social behavior • vocal learning • negative regulation of cell volume • positive regulation of long-term neuronal synaptic plasticity • brain morphogenesis • positive regulation of synapse structural plasticity • positive regulation of synaptic transmission, glutamatergic • dendritic spine morphogenesis • positive regulation of dendritic spine development • regulation of dendritic spine morphogenesis • vocalization behavior • postsynaptic density assembly • AMPA glutamate receptor clustering • NMDA glutamate receptor clustering • guanylate kinase-associated protein clustering • regulation of long-term synaptic potentiation • positive regulation of long-term synaptic potentiation • positive regulation of glutamate receptor signaling pathway • regulation of long term synaptic depression • positive regulation of excitatory postsynaptic potential • positive regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	85358	58234
Ensembl	ENSG00000251322	ENSMUSG00000022623
UniProt	Q9BYB0	Q4ACU6
RefSeq (mRNA)	NM_001080420	NM_021423
RefSeq (protein)	NP_277052	NP_067398
Location (UCSC)	Chr 22: 51.11 – 51.17 Mb	Chr 15: 89.5 – 89.56 Mb
PubMed search

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. 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.^[2]

Clinical significance

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

Interactions

SHANK3 has been shown to interact with ARHGEF7.^[5]

Mouse models

Mouse models of Shank3 include N-terminal knock-outs^[6][7] and a PDZ domain knock-out^[8] all of which also show social interaction deficits and variable other phenotypes. Most of the 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.^[9] 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.

References

1. "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3".
2. Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED (2002). "ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease". J. Neurochem. 81 (5): 903–10. doi:10.1046/j.1471-4159.2002.00931.x. PMID 12065602.
3. Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS (2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)". J. Med. Genet. 48 (11): 761–6. doi:10.1136/jmedgenet-2011-100225. PMID 21984749.
4. Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K (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". Am. J. Med. Genet. A 164A (3): 806–9. doi:10.1002/ajmg.a.36358. PMID 24375995.
5. Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E (May 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". J. Biol. Chem. 278 (21): 19220–9. doi:10.1074/jbc.M301052200. PMID 12626503.
6. 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". Hum. Mol. Genet. 20 (15): 3093–108. doi:10.1093/hmg/ddr212. PMC: 3131048. PMID 21558424.
7. 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 (2010). "Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication". Mol Autism 1 (1): 15. doi:10.1186/2040-2392-1-15. PMC: 3019144. PMID 21167025.
8. 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". Nature 472 (7344): 437–42. doi:10.1038/nature09965. PMC: 3090611. PMID 21423165.
9. Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G (2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature 530 (7591): 481–4. doi:10.1038/nature16971. PMID 26886798.

Further reading

• Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE (2013). "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients". Nature 503 (7475): 267–71. doi:10.1038/nature12618. PMID 24132240.
• Bangash MA, Park JM, Melnikova T, Wang D, Jeon SK, Lee D, Syeda S, Kim J, Kouser M, Schwartz J, Cui Y, Zhao X, Speed HE, Kee SE, Tu JC, Hu JH, Petralia RS, Linden DJ, Powell CM, Savonenko A, Xiao B, Worley PF (2011). "Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism". Cell 145 (5): 758–72. doi:10.1016/j.cell.2011.03.052. PMC: 3110672. PMID 21565394.
• Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (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 (2000). "The Shank family of scaffold proteins". J. Cell. Sci. 113 ( Pt 11) (11): 1851–6. 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 (1999). "Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density". J. Neurosci. 19 (15): 6506–18. PMID 10414979.
• Hirosawa M, Nagase T, Murahashi Y, Kikuno R, Ohara O (2001). "Identification of novel transcribed sequences on human chromosome 22 by expressed sequence tag mapping". DNA Res. 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 (2001). "Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome". Am. J. Hum. Genet. 69 (2): 261–8. doi:10.1086/321293. PMC: 1235301. PMID 11431708.
• Soltau M, Richter D, Kreienkamp HJ (2002). "The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42". Mol. Cell. Neurosci. 21 (4): 575–83. doi:10.1006/mcne.2002.1201. PMID 12504591.
• Bonaglia MC, Giorda R, Mani E, Aceti G, Anderlid BM, Baroncini A, Pramparo T, Zuffardi O (2006). "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". J. Med. Genet. 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 (2007). "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nat. Genet. 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 (2007). "Contribution of SHANK3 mutations to autism spectrum disorder". Am. J. Hum. Genet. 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 (2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature 530 (7591): 481–4. doi:10.1038/nature16971. PMID 26886798.

External links

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