Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress.
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.
Endocrine Reviews 07/1999; 20(3):279-307. · 19.93 Impact Factor
Article: The association of the D2S2944 124 bp allele with recurrent early onset major depressive disorder in women.[show abstract] [hide abstract]
ABSTRACT: Major depressive disorder (MDD) and substance use disorders (SUD) are complex behavioral disorders with 40-50% heritability. Recently, Zubenko and colleagues reported that the 124 bp allele of D2S2944, a tetranucleotide repeat marker on 2q35, is strongly associated with recurrent, early onset MDD (RE-MDD) and alcohol use disorders in women. To test this hypothesis, we examined the association of the 124 bp allele in a subset of 171 adoptees from the Iowa Adoption Studies, a population with high rates of MDD and SUD. We report that in our population, the 124 bp allele significantly associated with RE-MDD in women. There was slight evidence of an increased of SUD in women with the 124 bp allele with the rate of cannabis use disorders reaching statistical significance (P < 0.04) before correction for multiple comparisons. Given the history of prior studies implicating 2q35 as a locus encoding vulnerability to co-morbid alcoholism and depression, these findings strongly suggest that sequence variation conveying increased susceptibility to MDD and possibly SUD is in close proximity to D2S2944.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2003; 121B(1):39-43. · 3.70 Impact Factor
Article: Catecholaminergic cell lines from the brain and adrenal glands of tyrosine hydroxylase-SV40 T antigen transgenic mice.[show abstract] [hide abstract]
ABSTRACT: Brain (CATH.a) and adrenal (PATH.1 and PATH.2) cell lines have been established that synthesize abundant dopamine and norepinephrine and express the appropriate catecholaminergic biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase. The lines were derived from TH-positive tumors in transgenic mice carrying the SV40 T antigen oncogene under the transcriptional control of 773 base pairs of 5' flanking sequences from the rat TH gene. Although the lines continue to express T antigen, they exhibit neuronal properties such as neurofilaments and synaptophysin and lack glial intermediate filaments. Although in vivo TH is only expressed in postmitotic neurons in the CNS, the CATH.a line demonstrates that TH expression and continued cell division are not incompatible after oncogenic transformation.Journal of Neuroscience 04/1993; 13(3):1280-91. · 7.11 Impact Factor