Biology:SHANK3
 Generic protein structure example |
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. 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).[2] 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.[3]
Clinical significance
Mutations in this gene are associated with autism spectrum disorder.[4] This gene is often missing in patients with 22q13.3 deletion syndrome (Phelan-McDermid syndrome),[5] although not in all cases.[6]
Interactions
SHANK3 has been shown to interact with ARHGEF7.[7]
Mouse models
Mouse models of SHANK3 include N-terminal knock-outs[8][9] and a PDZ domain knock-out[10] 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.[11] 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
 | This section does not cite any external source. HandWiki requires at least one external source. See citing external sources. (August 2023) (Learn how and when to remove this template message) |
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 mutants also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein.
References
- ↑ "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85358.
- ↑ "The Shank family of scaffold proteins". Journal of Cell Science 113 ( Pt 11) (11): 1851–6. June 2000. doi:10.1242/jcs.113.11.1851. PMID 10806096.
- ↑ "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. June 2002. doi:10.1046/j.1471-4159.2002.00931.x. PMID 12065602.
- ↑ Brown, EA (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. PMID 30237867.
- ↑ "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. November 2011. doi:10.1136/jmedgenet-2011-100225. PMID 21984749.
- ↑ "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. March 2014. doi:10.1002/ajmg.a.36358. PMID 24375995.
- ↑ "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. May 2003. doi:10.1074/jbc.M301052200. PMID 12626503.
- ↑ "Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3". Human Molecular Genetics 20 (15): 3093–108. August 2011. doi:10.1093/hmg/ddr212. PMID 21558424.
- ↑ "Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication". Molecular Autism 1 (1): 15. December 2010. doi:10.1186/2040-2392-1-15. PMID 21167025.
- ↑ "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction". Nature 472 (7344): 437–42. April 2011. doi:10.1038/nature09965. PMID 21423165. PMC 3090611. Bibcode: 2011Natur.472..437P. http://dspace.mit.edu/bitstream/1721.1/87697/1/Feng_Shank3%20mutant.pdf.
- ↑ "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature 530 (7591): 481–4. February 2016. doi:10.1038/nature16971. PMID 26886798. Bibcode: 2016Natur.530..481M.
Further reading
- "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients". Nature 503 (7475): 267–71. November 2013. doi:10.1038/nature12618. PMID 24132240. Bibcode: 2013Natur.503..267S.
- "Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins". Neuron 23 (3): 583–92. July 1999. doi:10.1016/S0896-6273(00)80810-7. PMID 10433269.
- "The Shank family of scaffold proteins". Journal of Cell Science 113 ( Pt 11) (11): 1851–6. June 2000. doi:10.1242/jcs.113.11.1851. PMID 10806096.
- "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. August 1999. doi:10.1523/JNEUROSCI.19-15-06506.1999. PMID 10414979.
- "Identification of novel transcribed sequences on human chromosome 22 by expressed sequence tag mapping". DNA Research 8 (1): 1–9. February 2001. doi:10.1093/dnares/8.1.1. PMID 11258795.
- "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. August 2001. doi:10.1086/321293. PMID 11431708.
- "The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42". Molecular and Cellular Neurosciences 21 (4): 575–83. December 2002. doi:10.1006/mcne.2002.1201. PMID 12504591.
- "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". Journal of Medical Genetics 43 (10): 822–8. October 2006. doi:10.1136/jmg.2005.038604. PMID 16284256.
- "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nature Genetics 39 (1): 25–7. January 2007. doi:10.1038/ng1933. PMID 17173049.
- "Contribution of SHANK3 mutations to autism spectrum disorder". American Journal of Human Genetics 81 (6): 1289–97. December 2007. doi:10.1086/522590. PMID 17999366.
- "Adult restoration of Shank3 expression rescues selective autistic-like phenotypes". Nature 530 (7591): 481–4. February 2016. doi:10.1038/nature16971. PMID 26886798. Bibcode: 2016Natur.530..481M.
External links
PDB gallery | |
|---|---|
|
 |  |
