Neurodevelopmental disorders and SCN2A

Neurodevelopmental disorders (NDD) represent a broad spectrum of conditions disrupting typical neurological growth and development. One gene, SCN2A, has been closely linked to various disorders. Pathogenic variants in SCN2A are monogenic, meaning they originate from alterations in a single gene. However, the phenotypic manifestations of these variants — the observable physical and behavioral traits — show a high degree of variability, often puzzling clinicians and researchers alike. This has led to a comprehensive investigation into the complex genotype-phenotype correlations underlying SCN2A-related NDD.

Studying genetic modifiers

One way to unravel these complex correlations is to study genetic modifiers. These are genes that can impact the expression of another gene. In the context of rare driver mutations such as those in SCN2A, genetic modifiers can contribute to the considerable variability in disease phenotypes. A standard method to study this is using inbred rodent strains, which exhibit different genetic backgrounds and provide a unique opportunity to observe and analyze the influence of these backgrounds on disease-related phenotypes. Mice used in this research were obtained from the Mutant Mouse Resource & Research Centers (MMRRC), a trusted source for mouse models of human disease.

Development of a mouse model

The recent study developed a mouse model of the SCN2A-p.K1422E variant maintained as an isogenic line on the C57BL/6J (B6) strain. Upon initial characterization, the heterozygous Scn2aK1422E mice showed alterations in anxiety-related behavior and seizure susceptibility, a finding that provided a preliminary view of the phenotypes linked with the SCN2A mutation.

The researchers compared the neurobehavioral assays from mice on the B6 strain with those on a [DBA/2J×B6]F1 hybrid (F1D2) strain to explore how the genetic background could influence these phenotypes. The intriguing results showed that Scn2aK1422E mice displayed lower anxiety-like behavior than their wild-type counterparts. Interestingly, this effect was more pronounced on the B6 background than on the F1D2 background.

They also evaluated strain-dependent differences in seizure activity. Although there were no noticeable differences in the occurrence of rare spontaneous seizures between the two strains, the response to the chemo-convulsant kainic acid did show differences. This difference was not only in seizure generalization but also in the risk of lethality and varied based on both strain and sex of the mice.

Implications of the research

The implications of our research are significant. Continued exploration of strain-dependent effects in the Scn2aK1422E mouse model could highlight genetic backgrounds with unique susceptibility profiles. These insights would be precious for future studies, specifically, those focused on identifying specific traits associated with SCN2A-related NDD.

Moreover, by shedding light on the most penetrant phenotypes and potential modifier genes, researchers hope to unearth clues about the primary pathogenic mechanism of the K1422E variant. Such information is paramount for developing novel treatment strategies and personalized medicine approaches for patients with these challenging conditions. In conclusion, by tapping into the potential of mouse models, science can advance understanding of the genetic intricacies of SCN2A-related NDD.


View All News