Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania.
De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID).
Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014).
In this "<i>Perspectives</i>" article, we review and comment on current advances in Shank3 research and include some original data that show common Shank3 deficits in a number of seemingly unrelated human neurological disorders that include sporadic Alzheimer's disease (AD), autism spectrum disorder (ASD), bipolar disorder (BD), Phelan-McDermid syndrome (PMS; 22q13.3 deletion syndrome), and schizophrenia (SZ).
To characterize the zinc-induced Shank3 interactome, we performed various bioinformatic analyses that revealed significant associations of the interactome with subcellular compartments, including mitochondria, and brain disorders, such as bipolar disorder and schizophrenia.
We conclude that miR-7 binds to 3-prime untranslated regions of SHANK3 mRNA and causes the alteration of neuronal morphology and function, potentially playing a crucial role in the pathophysiological process of schizophrenia.
The SHANK3 gene encoding core scaffolding proteins at glutamatergic postsynapse is a typical dosage-sensitive gene, both deletions and duplications of which are associated with Phelan-McDermid syndrome, autism spectrum disorders, bipolar disorder, intellectual disability, or schizophrenia.
SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language.
As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.