Article

Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress.

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Molecular psychiatry (impact factor: 15.05). 04/2008; 14(4):390-7. DOI:10.1038/mp.2008.23
Source: PubMed

ABSTRACT Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.

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Keywords

clinical populations
 
CREB1 promoter co-segregates
 
early-onset MDD
 
employed plasmid constructs
 
familial subtype
 
female gonadal steroids
 
functional significance
 
gene-environment interactions
 
implicating CREB1
 
linkage
 
Major depressive disorder
 
major public health problem
 
mood disorders
 
noradrenergic neuronal cells
 
Previous genetic studies
 
rare G-to-A transition
 
significant evidence
 
simulated stress condition
 
transfection experiments
 
unipolar mood disorders
 

G S Zubenko