SHANK2

This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.[6]

It is thought that SHANK2 might play a role in synaptogenesis by attaching metabotropic glutamate receptors (mGluRs) to an existing pool of NMDA receptors (NMDA-R), bylinking to the NMDA-R through PSD-95, and the mGluRs through HOMER1.[7] An alternative hypothesis is that the Homer/Shank/GKAP/PSD-95 assembly mediates physical association of the NMDAR with IP3R/RYR and intracellular Ca2+ stores.

SHANK2 has been shown to interact with:

• ARHGEF7,[8]
• Cortactin,[9]
• DLG4,[10][11]
• DLGAP1,[10][11] and
• DNM2.[12]

Mutations in SHANK2 have been associated with autism spectrum disorder (ASD) and schizophrenia.[13] In particular, heterozygous loss-of-function mutations have a near-complete penetrance in ASD.[14] Neurons generated from people with ASD and SHANK2 mutations develop larger dendritic trees and more synaptic connections than those from healthy controls.[15] In addition, common mutations in SHANK2 have been linked to bipolar disorder.[16]

• The SHANK2 Foundation - non-profit supporting families and research into SHANK2 disorders