A novel mechanism to explain protein abnormalities in schizophrenia based on the flavivirus resistance gene.

The geographical distribution of schizophrenia was previously shown to correlate with the global distribution of tick-borne flaviviruses. The correlation suggests a natural resistance gene to flaviviruses could be involved in schizophrenia. The flavivirus resistance gene, Flv, a gene found in wild mice and certain in-bred strains, confers resistance to flaviviruses through the interaction of cellular proteins with the flaviviral 3' untranslated regions (UTRs). Although the sequence and product of Flv are unknown, translation elongation factor alpha-1 (EF-1) is a protein known to interact with the 3' UTR flavivirus RNA, forming some complexes with long half-lives that inhibit RNA growth. A study was performed to assess the homology between flaviviral UTRs, subunits of EF-1, and selected proteins reported as abnormal in schizophrenia. The UTRs of four flaviviruses with wide geographical and phylogenic distribution were manually translated. Using the National Biomedical Research Foundation protein databank, the amino acid sequences were correlated with the amino acid sequences of selected proteins. The amino acid sequences of the EF-1 subunits were then correlated with the same proteins. Similar amino acid correlations between the proteins, EF-1 subunits and viral UTRs suggest that translational pathophysiology resulting from the product of Flv can be postulated as the cause of protein abnormalities observed in schizophrenia.