Lithium is potent non-competitive inhibitor of an enzyme involved in the metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P(2)), a critical phosphoinositide (PI) that regulates signal transduction and synaptic vesicle function. Interestingly, a number of genes involved in the regulation of PtdIns-4,5-P(2) synthesis and dephosphorylation are found in regions of the genome previously mapped in bipolar disorder (BPD) including 10p, 18q, 21q, and 22q. One is PIK4CA, a member of the phosphatidylinositol 4-kinase family that phosphorylates PtdIns at the D4 position of the inositol ring as part of the PtdIns-4,5-P(2) synthetic pathway. PIK4CA maps to 22q11 in a region believed to contain a susceptibility gene for psychiatric disorders. Screening of two functional domains of PIK4CA and the promoter region resulted in the identification of 15 different polymorphisms. Rare variants at a consensus splice donor site and the promoter region were found in a total of three patients with BPD, three with schizophrenia (SZ) and only one control. Several common non-synonymous changes and a common single nucleotide polymorphism (SNP) at position -31 in the putative promoter were identified and analyzed in patients with BPD, SZ, and controls. There was no difference in the allele distribution in mentally ill subjects and controls for two variants, R2259C and E2079Q, both located in the PIK4CA catalytic domain. There was, however, a trend toward significance in the distribution of the -31 promoter genotypes in bipolar subjects and controls. Although the results of this analysis were modest, considering the heterogeneity of BPD and SZ and the hypothesis that BPD may be caused by abnormalities in genes that regulate PI-mediated phenomena in the brain, the polymorphisms we detected in the PIK4CA gene should be analyzed in a larger data set to help determine their significance in 22q11-linked mental disorders.
Copyright 2002 Wiley-Liss, Inc.