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 SHANK3gene on chromosome 22. 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. 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.
Mouse models of Shank3 include N-terminal knock-outs and a PDZ domain knock-out 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. 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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