SYNGAP1

SYNGAP1 is a human gene located on chromosome 6p21 that encodes the synaptic Ras GTPase-activating protein 1. The protein is a cytosolic enzyme that is recruited to postsynaptic density membranes via its N-terminal Ca²⁺/calmodulin-binding motif. SYNGAP1 functions as a regulator of the Ras/ERK signaling cascade in excitatory neurons, modulating AMPA receptor trafficking, dendritic spine morphology and synaptic plasticity. Variants that impair SYNGAP1 function lead to reduced synaptic strength and altered long‑term potentiation.

Genetic studies have identified heterozygous loss‑of‑function and nonsense mutations in SYNGAP1 as a cause of autosomal dominant intellectual disability. Clinically, affected individuals often present with developmental delay, speech impairment, autism spectrum traits, and in many cases epilepsy. Seizure types are variable and can range from focal to generalized. Neuroimaging typically shows normal brain structure, though mild cortical malformations have been reported.

The gene is highly expressed during early brain development and remains abundant in the hippocampus, cerebral cortex and cerebellum. SYNGAP1 interacts with the scaffold protein PSD‑95, the N‑Methyl‑D‑aspartate (NMDA) receptor complex and various kinases (e.g., CaMKII). Loss of SYNGAP1 disrupts the balance between synaptic excitation and inhibition, which is believed to underlie the neurodevelopmental phenotypes.

Therapeutic strategies are largely symptomatic, focusing on seizure control and developmental support. Experimental models have explored pharmacological activation of downstream signaling (e.g., ERK modulators) and synaptic enhancers, with gradual improvement in behavioral deficits in mouse models. As of now, no specific gene‑based therapy has been approved, but clinical trials targeting synaptic plasticity pathways are underway.