SYNGAP1
Mutations in the SYNGAP1 gene cause a syndromic neurodevelopmental disorder characterized by intellectual disability, epilepsy, delayed speech and motor development, and features of autism spectrum disorder. This condition, referred to as SYNGAP1-related intellectual disability, is caused primarily by haploinsufficiency—where a single functional copy of the gene is insufficient for normal neurological development. Most identified mutations are de novo and result in loss of function.
SYNGAP1 encodes SynGAP, a critical protein found in the postsynaptic density of excitatory synapses. SynGAP regulates small GTPases such as Ras and Rap, thereby modulating downstream signaling pathways that influence synaptic plasticity, dendritic spine morphology, and neuronal connectivity. This regulation is essential for normal learning, memory, and behavior.
Due to its central role in excitatory synapse function and plasticity, SYNGAP1 is considered a high-confidence gene for intellectual disability and autism, and ongoing research is exploring it as a potential therapeutic target in these conditions.
Biological Function
- SynGAP is a critical regulator of long-term potentiation and long-term depression at excitatory synapses. It modulates synaptic strength by controlling the activity of small GTPases like Ras and Rap, which are central to AMPA receptor trafficking and synaptic efficacy.
- SynGAP is one of the most abundant proteins in the postsynaptic density. It interacts with scaffolding proteins like PSD-95 via PDZ domain interactions, contributing to PSD structure and the molecular organization of synapses.
- Different C-terminal splice variants (e.g., α1, α2, β, γ) exhibit distinct subcellular localizations and functions. SynGAP-α1 is synapse-specific and crucial for plasticity, while SynGAP-β promotes dendritic growth and is found in non-synaptic locations.
- SynGAP undergoes phosphorylation-dependent dispersal from dendritic spines upon synaptic activation. This relieves its inhibitory effect on Ras signaling, enabling synaptic strengthening through AMPA receptor recruitment.
- SynGAP regulates learning, memory, and behavior. Loss of function in mouse models recapitulates symptoms seen in SYNGAP1-related intellectual disability, including seizures, hyperactivity, and working memory deficits.
- SYNGAP1 deficiency disrupts normal developmental timing of synapse formation in human neurons, leading to early maturation and altered circuit integration, which may underlie intellectual disability and autism.