Biology:SHANK3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
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

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

  1. ↑ "Entrez Gene: SHANK3 SH3 and multiple ankyrin repeat domains 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85358. 
  2. ↑ "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. 
  3. ↑ "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. 
  4. ↑ 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. 
  5. ↑ "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. 
  6. ↑ "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. 
  7. ↑ "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. 
  8. ↑ "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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "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

External links



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