SH3 and multiple ankyrin repeat domains protein 2 (SHANK2) (SHANK2)

SH3 and multiple ankyrin repeat domains protein 2 (SHANK2) is a critical scaffolding protein located in the postsynaptic density (PSD) of excitatory synapses in the central nervous system (UniProt Q9UPX8). It acts as a master organizer by bridging neurotransmitter receptors, such as NMDA and metabotropic glutamate receptors, to the actin cytoskeleton, thereby facilitating signal transduction and synaptic plasticity (PubMed: 31036957). SHANK2 mRNA is the precursor for this protein, and its precise regulation is essential for normal brain development and cognitive function. Mutations, deletions, or copy number variations in the SHANK2 gene are strongly associated with neurodevelopmental disorders, most notably autism spectrum disorder (ASD) and intellectual disability (PubMed: 20473310). Because SHANK2 deficiency leads to synaptic dysfunction, its mRNA is considered a potential therapeutic target for RNA-based modalities like antisense oligonucleotides (ASOs) aimed at restoring protein levels (PubMed: 22581228). Currently, there are no FDA-approved drugs that directly target SHANK2 mRNA, though research into gene-modulating therapies is ongoing. Therapeutic development faces challenges such as the need for precise dosage control to avoid hyperexcitability and the difficulty of delivering large molecules across the blood-brain barrier (PubMed: 31036957).

Other names

Proline-rich synapse-associated protein 1ProSAP1Cortactin-binding protein 1CortBP1AUTS17SH3 and multiple ankyrin repeat domains 2

Modulation of protein expression levels through antisense oligonucleotides (ASOs) or RNA interference (RNAi) to address haploinsufficiency or pathogenic splicing.