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.
Zhou
Xianjin
X
Department of Psychiatry, University of California, San Diego, CA 92093, USA.
Barrett
Thomas B
TB
Kelsoe
John R
JR
D000483:Alleles; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics; D051706:Sp4 Transcription Factor / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
C497124:SP4 protein, human; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human