SH3 and multiple ankyrin repeat domains 3 (SHANK3) pre-messenger RNA (SHANK3 pre-mRNA)

SH3 and multiple ankyrin repeat domains 3 (SHANK3) pre-messenger RNA and messenger RNA are critical therapeutic targets for addressing haploinsufficiency in neurodevelopmental disorders. The SHANK3 gene encodes a master scaffolding protein essential for the structural and functional organization of the postsynaptic density in excitatory synapses (UniProt Q9BYB0). Mutations or deletions of one allele of SHANK3 lead to Phelan-McDermid syndrome and are a significant genetic cause of autism spectrum disorder (PubMed: 35110414). Therapeutic strategies focusing on the pre-mRNA or mRNA aim to restore protein levels by modulating alternative splicing or enhancing the stability of the transcript. Specifically, antisense oligonucleotides (ASOs) are being designed to prevent the inclusion of non-productive exons or to promote the translation of the remaining healthy allele (PubMed: 31601711). Precise titration of SHANK3 levels is vital, as both deficiency and overabundance of the protein are associated with distinct neurological pathologies, including manic-like behaviors in cases of overexpression.

Other names

Proline-rich synapse-associated protein 2ProSAP2SH3 and multiple ankyrin repeat domains 3 mRNASHANK3 mRNASCZD15

Targeted Augmentation of Nuclear Gene Expression (TANGO) to increase productive mRNA levels; Splice modulation to prevent non-productive splicing; RNA stabilization to increase protein translation.