SHANK3

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.[5] Additional isoforms have been described for this gene but they have not yet been experimentally verified.

SHANK3
Identifiers
AliasesSHANK3, DEL22q13.3, PROSAP2, PSAP2, SCZD15, SPANK-2, SH3 and multiple ankyrin repeat domains 3
External IDsOMIM: 606230 MGI: 1930016 HomoloGene: 75163 GeneCards: SHANK3
Gene location (Human)
Chr.Chromosome 22 (human)[1]
Band22q13.33Start50,674,415 bp[1]
End50,733,298 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

85358

58234

Ensembl

ENSG00000251322

ENSMUSG00000022623

UniProt

Q9BYB0

Q4ACU6

RefSeq (mRNA)

NM_001080420
NM_001372044

NM_021423

RefSeq (protein)

NP_277052

NP_067398

Location (UCSC)Chr 22: 50.67 – 50.73 MbChr 15: 89.5 – 89.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 sterile α motif domain (SAM).[6] 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.[7]

Clinical significance

Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome,[8] although not in all cases.[9]

Interactions

SHANK3 has been shown to interact with ARHGEF7.[10]

Mouse models

Mouse models of SHANK3 include N-terminal knock-outs[11][12] and a PDZ domain knock-out[13] 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.[14] 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. GRCh38: Ensembl release 89: ENSG00000251322 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000022623 - Ensembl, May 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.
  5. "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3".
  6. Sheng M, Kim E (June 2000). "The Shank family of scaffold proteins". Journal of Cell Science. 113 ( Pt 11): 1851–6. PMID 10806096.
  7. Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED (June 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.
  8. Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS (November 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.
  9. Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K (March 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.
  10. 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". The Journal of Biological Chemistry. 278 (21): 19220–9. doi:10.1074/jbc.M301052200. PMID 12626503.
  11. 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.
  12. 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 (December 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.
  13. 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. doi:10.1038/nature09965. PMC 3090611. PMID 21423165.
  14. Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G (February 2016). "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature. 530 (7591): 481–4. doi:10.1038/nature16971. PMC 4898763. PMID 26886798.

Further reading
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