SHANK3
SH3 and multiple ankyrin repeat domains 3, also known as SHANK3, is a human gene on chromosome 22.[1]
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. Mutations in this gene are a cause of autism spectrum disorder (ASD) which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene are a major causitive factor in the neurological symptoms of 22q13.3 deletion syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq]
Interactions
SHANK3 has been shown to interact with ARHGEF7.[2]
Mouse Models
Bangash et al. created a gain-of-function transgenic mouse bearing a deletion at the C terminus of Shank3 that mimics clinical mutations and define a biochemical pathway linking mutant Shank3 to the proteasomal degradation of Shank3 and NMDA type glutamate receptors subunit NR1. PMID 21565394 The heterozygous mutant mice display autism-like behavioral deficits and also exhibit schizophrenia-like phenotypes, consistent with altered glutamate receptor function.[3] Consistent with this, the mice have deficits in NMDA LTP, LTD and enhanced mGluR LTD similar to Fragile-X. These results suggest that NMDA receptor degradation could be a shared feature of both Autism and Schizophrenia.
Other mouse models of Shank3 include N-terminal knock-outs PMID 21558424 and PMID 21167025 and a PDZ domain knock-out PMID 21423165 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.
References
- ^ "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85358.
- ^ Park, Eunhye; Na Moonseok, Choi Jeonghoon, Kim Seho, Lee Jae-Ran, Yoon Jiyoung, Park Dongeun, Sheng Morgan, Kim Eunjoon (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. (United States) 278 (21): 19220–9. doi:10.1074/jbc.M301052200. ISSN 0021-9258. PMID 12626503.
- ^ Bangash, M Ali; 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. (May. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3110672.
Further reading
- 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3110672.
- 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): 1851–6. PMID 10806096.
- Boeckers TM, Kreutz MR, Winter C, et al. (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, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1235301.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Soltau M, Richter D, Kreienkamp HJ (2003). "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.
- Wilson HL, Wong AC, Shaw SR, et al. (2003). "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms.". J. Med. Genet. 40 (8): 575–84. doi:10.1136/jmg.40.8.575. PMC 1735560. PMID 12920066. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1735560.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Bonaglia MC, Giorda R, Mani E, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2563164.
- Durand CM, Betancur C, Boeckers TM, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2082049.
- Moessner R, Marshall CR, Sutcliffe JS, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2276348.
External links
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PDB gallery
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2f3n: Crystal Structure of the native Shank SAM domain.
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2f44: Crystal Structure of the Zinc-bound Shank SAM domain
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