SHANK3

SHANK3
Identifiers
Aliases	SHANK3, DEL22q13.3, PROSAP2, PSAP2, SCZD15, SPANK-2, SH3 and multiple ankyrin repeat domains 3
External IDs	OMIM: 606230; MGI: 1930016; HomoloGene: 75163; GeneCards: SHANK3; OMA:SHANK3 - orthologs
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.33 Start 50,674,415 bp[1] End 50,733,212 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 E3 Start 89,383,826 bp[2] End 89,444,464 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum cerebellar vermis lateral nuclear group of thalamus spleen cardiac muscle tissue of right atrium apex of heart entorhinal cortex postcentral gyrus sural nerve myocardium of left ventricle Top expressed in medial dorsal nucleus dentate gyrus of hippocampal formation granule cell medial geniculate nucleus olfactory tubercle cerebellar cortex superior frontal gyrus primary visual cortex lobe of cerebellum lateral geniculate nucleus cerebellar vermis More reference expression data BioGPS More reference expression data
Gene ontology Molecular function SH3 domain binding scaffold protein binding zinc ion binding protein C-terminus binding protein binding synaptic receptor adaptor activity actin binding ionotropic glutamate receptor binding protein self-association signaling receptor complex adaptor activity Cellular component cytoplasm postsynaptic membrane cell projection membrane plasma membrane dendritic spine synapse cell junction ciliary membrane neuron spine neuron projection postsynaptic density cytosol extrinsic component of cytoplasmic side of plasma membrane ionotropic glutamate receptor complex dendrite Biological process positive regulation of long-term synaptic potentiation positive regulation of synapse structural plasticity NMDA glutamate receptor clustering regulation of long-term synaptic depression positive regulation of glutamate receptor signaling pathway postsynaptic density assembly negative regulation of actin filament bundle assembly negative regulation of cell volume positive regulation of AMPA receptor activity memory learning positive regulation of dendritic spine development MAPK cascade striatal medium spiny neuron differentiation AMPA glutamate receptor clustering dendritic spine morphogenesis vocal learning vocalization behavior adult behavior positive regulation of synaptic transmission, glutamatergic positive regulation of long-term neuronal synaptic plasticity regulation of long-term synaptic potentiation positive regulation of excitatory postsynaptic potential social behavior guanylate kinase-associated protein clustering synapse assembly regulation of dendritic spine morphogenesis brain morphogenesis axon guidance synaptic assembly at neuromuscular junction long-term potentiation regulation of AMPA receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 15: 89.38 – 89.44 Mb PubMed search [3] [4]
Wikidata
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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.

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]

Mutations in this gene are associated with autism spectrum disorder.^[8] This gene is often missing in patients with 22q13.3 deletion syndrome (Phelan–McDermid syndrome),^[9] although not in all cases.^[10]

SHANK3 has been shown to interact with ARHGEF7.^[11]

Mouse models of SHANK3 include N-terminal knock-outs^[12][13] and a PDZ domain knock-out^[14] 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.^[15] 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.

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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.^[16] These mutants also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein.

• GeneReviews/NCBI/NIH/UW entry on Phelan-McDermid or 22q13.3 deletion syndrome