Frequently Asked Questions
If you have any questions on the SGM server or SynGAP1 missense mutations, please contact us.
What is SynGAP?
SynGAP, short for Synaptic GTPase-Activating Protein, is a vital signaling protein at the postsynaptic density of excitatory neurons in the forebrain. SynGAP negatively regulates small G proteins or GTPases, by accelerating the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) by the enzymes. Structurally SynGAP belongs to RasGAP proteins but it is also able to control Rap1 activity. SynGAP influences the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Lastly, SynGAP plays a vital role in synaptic plasticity mediated by N-methyl-D-aspartate (NMDA) glutamate receptors.
What are SynGAP-Related NSID Disorders?
SynGAP-related NSID (Non-Syndromic Intellectual Disability) disorders include intellectual disability, hypotonia, ataxia, epilepsy, and motor skill delays. The severity of the symptoms varies between patients and due to their broad spectrum, the disease remains difficult to diagnose even with the help of modern genomic sequencing. The disease state, which becomes apparent in early childhood, is caused by non-inherited de novo mutations to the SYNGAP1 gene.
What are SynGAP Missense Mutations and Variants?
A missense mutation occurs when a single nucleotide change lead into a different amino acid being incorporated into the protein structure. The impact of a missense mutation depends on the specific substitution and its effect on protein structure and function. Missense mutations can lead to various genetic disorders and diseases, whose effect or severity can vary. Different missense mutations constitute different missense variants. Several missense mutations are known for SynGAP, but no clinical status has not been assigned for a clear majority of them in the ClinVar so far.
What Part of the SynGAP Structure Is Used in the Modeling Work?
The full SynGAP structure has not been determined as of yet. Only a C2-GAP fragment (PDB: 3BXJ) and the coiled-coil trimer (PDB: 5JXC) of SynGAP are known. However, AlphaFold2 from Google’s DeepMind provides a 3D model of SynGAP (AF-Q96PV0-F1-model_v3.pdb), whose N-terminal portion (residues 198-730), including the GAP and C2 domains and part of the PH domain, was used for the SynGAP missense modeling work.
The image was created with the assistance of DALL·E 3 via MS Copilot.