Promoter variant in the GRK3 gene associated with bipolar disorder alters gene expression.

BACKGROUND: We have previously reported a single nucleotide polymorphism (P-5, G-384A) in the proximal promoter of the gene for G protein receptor kinase 3 (GRK3) that was associated with bipolar disorder in two independent samples. In this study, we examined whether the G-384A variant has a functional effect on GRK3 transcription. METHODS: Electrophoretic mobility shift assays were conducted using nuclear extracts from both Hela cells and adult mouse cortex. Transcriptional function was also examined using a dual luciferase reporter system transfected into in vitro human neuroblastoma cells and cultured mouse cortical neurons. RESULTS: The G-384A variant abolished or reduced the formation of DNA-protein complexes using nuclear extract from both HeLa cells and adult mouse cortical neuron cells. However, gene expression was significantly enhanced by G-384A in both in vitro human neuroblastoma cells and cultured mouse cortical neurons. CONCLUSIONS: These data suggest that the G-384A SNP in the promoter of human GRK3 gene represents an important functional variant. The G-384A variant may alter binding of Sp1/Sp4 transcription factors resulting in an increase in gene transcription and an increase in vulnerability to bipolar disorder.