3D modelling reveals how small missense mutations in the SynGAP1 protein can cause a rare childhood neurological disorder

Sometimes, a change in just a single nucleotide in the genome can lead to significant health problems and the onset of disease. When such a change replaces one amino acid with another in a protein encoded by an important gene, it is referred to as a missense mutation. Such a change may seem insignificantly small at first sight, but the actual effects can be very large.

One gene that is particularly sensitive to such changes is SYNGAP1, which encodes SynGAP1 protein that is abundant in neurons of the forebrain. Reduced expression from even a single allele of this gene is enough to cause a severe neurological disorder.

The clinical picture is diverse: common symptoms include varying degrees of intellectual disability, epilepsy and features of the autism spectrum.

A single amino acid substitution in a long amino acid chain does not always result in major functional changes. In one position, the change may be harmless, but in another it may be devastating to the protein’s vital function.

For this reason, accurately assessing the impact of missense mutations requires computational methods capable of evaluating how such changes affect the protein’s structure in particular.

Pekka Postila and his research group have received a total of 230,000 dollars in funding from the California-based Cure SYNGAP1 Foundation to investigate SynGAP1 missense mutations. The aim of the research is to improve the diagnostics of SYNGAP1 missense variants by leveraging advanced computational structural analysis.

In computer simulations, the atoms of amino acids are represented as spheres, and the bonds between them behave like small springs. This allows the protein model to move and “live” much like it does inside actual cells. Using these calculations, it is possible to identify which missense mutations are likely to alter the protein’s structure in a critical way and thereby cause the neurological disorder.

Modelling helps to identify a rare childhood neurological disorder caused by missense mutations of SynGAP1 protein

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3D modelling reveals how small missense mutations in the SynGAP1 protein can cause a rare childhood neurological disorder

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