Shank3/ProSAP2 is one of three members of the Shank/ProSAP family of proteins which contain five conserved protein domains – an ankyrin repeat (ANK), a Src homology 3 (SH3), a PSD-95/Discs large/ZO-1 (PDZ), a proline-rich region containing homer- and cortactin-binding sites (Pro), and a sterile alpha motif (SAM)¹. Shank proteins localize in the postsynaptic density (PSD) of excitatory synapses where they function as master scaffolding proteins by interacting directly or indirectly with various proteins, including major types of glutamate receptors – NMDARs, AMPARs, and mGluRs – via different domains². Shank3 plays important roles in the formation, maturation, and maintenance of synapses³.

Shank3 is expressed abundantly in heart and moderately in brain (including the cortex, hippocampus and cerebellum) and spleen⁴.

Human genetic studies strongly support the notion that molecular defects of Shank3 contribute to autism spectrum disorders (ASD) which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests⁵. In addition, Shank3 mutations were also reported in patients with childhood-onset schizophrenia and intellectual disability⁶.

Furthermore, haplo insufficiency of Shank3 gene causes a developmental disorder, 22q13.3 deletion syndrome (known as Phelan–McDermid syndrome), that is characterized by severe expressive language and speech delay, hypotonia, global developmental delay, and autistic behavior³.