Physicochemical property changes of amino acid residues that accompany missense mutations in SCN1A affect epilepsy phenotype severity

Background: Several different missense mutations in the voltage-gated sodium channel subunit gene SCN1A have been identified in epileptic patients with benign phenotype and with severe phenotype. However, the reason why similar missense mutations in SCN1A resulting in different phenotypes has not yet been fully clarified. Objective: To clarify the phenotype-genotype relationship in SCN1A, we performed a meta-analysis to quantitatively determine the effect of amino acid (AA) residue substitutions in SCN1A on severity phenotype using physico-chemical property indices of AA, which have been discussed in the context of the molecular evolution of proteins. Methods: We searched PubMed for articles and extracted information about localization and types of SCN1A missense mutations in patients with benign and severe epileptic syndromes, and also extracted detailed information. Results: Meta-analysis quantitatively revealed that physico-chemical properties of several AAs significantly affected epilepsy phenotype severity. It showed that missense mutations decreasing protein hydrophobicity were significantly associated with severe epilepsy phenotypes. The meta-analysis showed that the phenotype severity of SCN1A missense mutations in the transmembrane domains of SCN1A (128/155; 82.6%) could be predicted with high sensitivities and positive predict values using the physico-chemical property changes, which indicated the possibility of phenotype prediction for entirely new missense mutations by the analysis methods. Conclusion: The results showed that changes in the physico-chemical properties of AA residues affected both the phenotype and clinical symptoms of patients with SCN1A missense mutations. This meta-analysis study provides new insights into SCN1A gene functions and a new strategy for genetic diagnosis, genetic counselling, and epilepsy treatment.