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 SHANK3gene on chromosome 22.[1] Additional isoforms have been described for this gene but they have not yet been experimentally verified.
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]
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 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.
↑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. PMID12065602.
↑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. PMID21984749.
↑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. PMID24375995.
↑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. PMID12626503.
↑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. PMID26886798.
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. PMID24132240.
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. PMID10433269.
Sheng M, Kim E (2000). "The Shank family of scaffold proteins". J. Cell Sci. 113 ( Pt 11) (11): 1851–6. PMID10806096.
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. PMID10414979.
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. PMID11258795.
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. PMID26886798.
