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
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.33 Start 50,674,415 bp[1] End 50,733,298 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 E3 Start 89,499,623 bp[2] End 89,560,261 bp[2]
RNA expression pattern Bgee Top expressed in cerebellar vermis cerebellum cerebellar hemisphere prefrontal cortex temporal lobe caudate nucleus sural nerve 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 GO:0001948 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 GO:0097483, GO:0097481 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 synaptic 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: 89.5 – 89.56 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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).^[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]

Clinical significance[]

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

Interactions[]

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

Mouse models[]

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.

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 mutant also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein.

References[]

Further reading[]

External links[]

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