Wei J, etal., Schizophr Res. 1996 Oct 18;22(1):77-80.
Intron 9 of the human dopamine beta-hydroxylase (DBH) gene was amplified using a long PCR procedure in unrelated patients with schizophrenia and unrelated control subjects. MspI digestion of the PCR fragments showed a two allele polymorphism. A1 and A2 Kruskal-
Wallis analysis revealed a significant difference in serum DBH activity among the three groups carrying the A1/A2 genotype, the drug-free and drug treated patients, and the control subjects (H = 12.2, df = 2, p < 0.005), and also a significant difference among the three subgroups of drug-treated patients carrying the genotype of A1/A1, A2/A2 or A1/A2 (H = 10.4, df = 2, p < 0.01). The present results suggest that the MspI polymorphic site in intron 9 of the human DBH gene may be associated with alterations of DBH activity in schizophrenia and with the influence of neuroleptic drugs on the DBH activity as well.
Old Believers of the Tyumen oblast have been studied compared with a control sample of Russian residents of the city of Novosibirsk. The former are a unique subpopulation, which has been relatively isolated from the rest of Russians in central and northern regions of Russia due to religious reasons
since the middle of the 17th century. Polymorphisms in the genes for glycoprotein ITGB3, dopamine-beta-hydroxylase (DBH), and chemokine receptor CCR2 and two mutations in the c-fms gene have been analyzed. The populations are only similar in the c-fms indel. The frequencies of the rare alleles of CCR2, ITGB3, and 3'UTR of c-fms in the Old Believers are lower than in the sample of Novosibirsk Russians, and the rare allele of DBH is more frequent. A significant negative correlation is observed between DBH and CCR2 (r =-0.88; df = 4; P < 0.023). Apparently, these differences are related to the long-term isolation of Old Believers. This assumption is consistent with the fact that the levels of heterozygosity for most loci in Old Believers are lower than in Novosibirsk Russians.
Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH
pan>, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.
Kim Y, etal., Nutr Res Pract. 2010 Aug;4(4):270-5. Epub 2010 Aug 31.
Catecholamines are among the first molecules that displayed a kind of response to prolonged or repeated stress. It is well established that long-term stress leads to the induction of catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH
-weight:700;'>DBH) in adrenal medulla. The aim of the present study was to evaluate the effects of ginseng on TH and DBH mRNA expression. Repeated (2 h daily, 14 days) immobilization stress resulted in a significant increase of TH and DBH mRNA levels in rat adrenal medulla. However, ginseng treatment reversed the stress-induced increase of TH and DBH mRNA expression in the immobilization-stressed rats. Nicotine as a ligand of the nicotinic acetylcholine receptor (nAChR) in adrenal medulla stimulates catecholamine secretion and activates TH and DBH gene expression. Nicotine treatment increased mRNA levels of TH and DBH by 3.3- and 3.1-fold in PC12 cells. The ginseng total saponin exhibited a significant reversal in the nicotine-induced increase of TH and DBH mRNA expression, decreasing the mRNA levels of TH and DBH by 57.2% and 48.9%, respectively in PC12 cells. In conclusion, immobilization stress induced catecholamine biosynthetic enzymes gene expression, while ginseng appeared to restore homeostasis via suppression of TH and DBH gene expression. In part, the regulatory activity in the TH and DBH gene expression of ginseng may account for the anti-stress action produced by ginseng.
Fernandez F, etal., J Neurol Sci. 2006 Dec 21;251(1-2):118-23. Epub 2006 Nov 7.
Migraine is a debilitating neurological disorder, affecting 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is unclear. Our previous work has investigated dopamine related migraine candidate genes and has rep
orted a significant allelic association with migraine of a microsatellite localised to the promoter region of the dopamine beta-hydroxylase (DBH) gene. The present study performed an association analysis in a larger population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining two different genetic DBH polymorphisms (a functional insertion/deletion promoter and a coding SNP A444G polymorphism). Although no significant association was found for the SNP polymorphism, the results showed a significant association between the insertion/deletion variant and disease (chi(2)=8.92, P=0.011), in particular in migraine with aura (chi(2)=11.53, P=0.003) compared to the control group. Furthermore, the analysis of this polymorphism stratified by gender, revealed that male individuals with the homozygote deletion genotype had three times the risk of developing migraine, compared to females. The DBH insertion/deletion polymorphism is in linkage disequilibrium with the previously reported migraine associated DBH microsatellite and this insertion/deletion polymorphism is functional, which may explain a potential role in susceptibility to migraine.
Chen H, etal., Medicine (Baltimore). 2015 Nov;94(47):e2012. doi: 10.1097/MD.0000000000002012.
Some epidemiological studies have investigated the relationship between genetic polymorphisms of DRD2, COMT, DBH, and MAO-A and migraine susceptibility, but the results are still inconsistent. Thus, our aim was to further assess the association through a meta-a
nalysis.We examined 5 single nucleotide polymorphisms (SNPs) in 4 genes, including DRD2 rs1799732 and rs6275, DBH rs7239728, MAI-A-VNTR, and COMT rs4680, and performed a meta-analysis of 11 published case-control studies including 3138 cases and 4126 controls. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association between the 5 genetic polymorphisms and migraine susceptibility.There was no significant relationship between migraine susceptibility and 4 genetic polymorphisms of DRD2 rs1799732 and rs6275, DBH rs7239728, and MAO-A-VNTR. Nevertheless, decreased risk of migraine was observed to be in association with COMT rs4680 polymorphism in overall analysis (AA vs. GG + GA: OR = 0.76, 95% CI = 0.60-0.97, PHet > 0.642, I = 0), and in Caucasian group after subgroup analysis (AA vs. GG + GA: OR = 0.75, 95% CI = 0.58-0.96, PHet > 0.433, I = 0).Studied polymorphisms of DRD2, DBH, and MAO-A genes may not be associated with migraine susceptibility. However, COMT rs4680 polymorphism may decrease the risk of migraine, especially in Caucasians. The failure to evaluate environmental influence and provide adjusted effect size estimates highlights the need for additional studies in a large number to take these factors into consideration, thus better elucidating the role of the genes tested in migraine.
We used mice deficient in dopamine beta-hydroxylase [Dbh(-/-)] and their littermate controls [Dbh(+/-)] to examine the role of epinephrine (Epi) and norepinephrine (NE) in the maintenance of cardiovascular parameters during
7 days of caloric restriction and acute exposure to environmental stress. Cardiovascular parameters of the mice were monitored using blood pressure radiotelemeters at an ambient temperature of 29 degrees C. Under normal conditions, Dbh(-/-) mice had a low heart rate, were severely hypotensive, and displayed an attenuated circadian blood pressure rhythm. Upon 50% caloric restriction, Dbh(+/-) mice exhibited decreases in heart rate and mean blood pressure. However, the blood pressures of Dbh(-/-) mice did not fall significantly in response to caloric restriction, and the bradycardia associated with caloric restriction was attenuated in these mice. In response to an open-field test, the blood pressure and heart rate of Dbh(+/-) mice increased substantially and rapidly, whereas Dbh(-/-) mice had blunted changes in blood pressures and no change in heart rate. These data suggest a primary role of Epi and NE in mediating the hypotension induced by dieting. Furthermore, Epi and NE play a smaller, but still significant, role in the bradycardia induced by caloric restriction. In contrast, Epi and NE are required for the tachycardia in an open field but are not required for the increase in blood pressure.
As the enzyme dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DbetaH (DBH) was applied to explore the geneti
c background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.
Levels of the enzyme dopamine beta-hydroxylase (DbetaH) in the plasma and cerebrospinal fluid (CSF) are closely related biochemical phenotypes. Both are under strong genetic control. Linkage and association studies suggest the structural gene encoding DbetaH (locus name, DBH
;'>DBH) is a major locus influencing plasma activity of DbetaH. This study examined relationships of DBH genotype determined at two polymorphic sites (a previously described GT repeat, referred to as the DBH STR and a single-base substitution at the 3' end of DBH exon 2, named DBH*444 g/a), to CSF levels of DbetaH protein in European-American schizophrenic patients, and to plasma DbetaH activity in European-American patients with mood or anxiety disorders. We also investigated linkage disequilibrium (LD) between the polymorphisms in the pooled samples from those European-American subjects (n=104). Alleles of DBH*444 g/a were associated with differences in mean values of CSF DbetaH levels. Alleles at both polymorphisms were associated with plasma DbetaH activity. Significant LD was observed between respective alleles with similar apparent influence on biochemical phenotype. Thus, allele A3 of the DBH STR was in positive LD with DBH*444a, and both alleles were associated with lower plasma DbetaH activity. DBH STR allele A4 was in positive LD with DBH*444 g, and both alleles were associated with higher plasma DbetaH activity. The results confirm that DBH is a major quantitative trait locus for plasma DbetaH activity, and provide the first direct evidence that DBH also influences CSF DbetaH levels. Both polymorphisms examined in this study appear to be in LD with one or more functional polymorphisms that mediate the influence of allelic variation at DBH on DbetaH biochemical phenotypic variation
Huang JL, etal., Oncotarget. 2015 Oct 20;6(32):33791-804. doi: 10.18632/oncotarget.5667.
Accumulating evidence supports an important role for the hepatitis B virus x protein (HBx) in the pathogenesis of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC), but the underlying mechanisms are not entirely clear. Here, we identified a novel long noncoding RNA (lncRNA) DBH
'font-weight:700;'>DBH-AS1 involved in the HBx-mediated hepatocarcinogenesis. The levels of DBH-AS1 were positively correlated with hepatitis B surface antigen (HBsAg) and tumor size in HCC tissues. Functionally, transgenic expression of DBH-AS1 significantly enhanced cell proliferation and tumorigenesis, whereas short hairpin RNA knockdown of DBH-AS1 caused an inhibition of cell proliferation. Mechanistically, overexpression of DBH-AS1 induced cell cycle progression by accelerating G1/S and G2/M transition concomitantly with upregulation of CDK6, CCND1, CCNE1 and downregulation of p16, p21 and p27. We also found that enhanced DBH-AS1 expression inhibited serum starvation-induced apoptosis of HCC cells. In contrast, suppressed DBH-AS1 expression had opposite effects. Furthermore, DBH-AS1 was shown to activate MAPK pathway. We also provide evidence that DBH-AS1 could be significantly induced by HBx protein and markedly down-regulated by p53. Thus, we concluded that DBH-AS1 can be induced by HBx and inactivated by p53, and consequently promote cell proliferation and cell survival through activation of MAPK signaling in HCC. Our study suggests that DBH-AS1 acts as an oncogene for HCC.
Previous data have strongly implicated hindbrain catecholamine/neuropeptide Y (NPY) coexpressing neurons as key mediators of the glucoprivic feeding response. Catecholamine/NPY cell bodies are concentrated in the A1 and caudal C1 cell cluster (A1/C1) in the ventrolateral medulla, a region highly sen
sitive to glucoprivic challenge. To further investigate the importance of this catecholamine subpopulation in glucoregulation, we used small interfering RNA (siRNA) technology to produce a targeted gene knockdown of NPY and dopamine-beta-hydroxylase (DBH), a catecholamine biosynthetic enzyme. Unilateral injection of NPY siRNA and DBH siRNA (0.02 nmol each) both significantly inhibited expression of the targeted genes up to 2 d, as revealed by real-time PCR, and reduced protein expression up to 8 d, as revealed by immunohistochemistry, compared with the control nontargeting siRNA (ntRNA) side. Subsequently, targeted siRNA or control ntRNA was injected bilaterally into A1/C1 and responses to 2-deoxy-D-glucose (2DG; 200 mg/kg)-induced glucoprivation were tested 3-7 d later. Silencing of either Npy or Dbh alone did not reduce glucoprivic feeding or hyperglycemic responses, compared with responses of ntRNA-injected controls. In contrast, simultaneous silencing of both Npy and Dbh reduced 2DG-induced feeding by 61%. Neither the hyperglycemic response to 2DG nor feeding elicited by mercaptoacetate (68 mg/kg)-induced blockade of fatty acid oxidation ("lipoprivic feeding") was reduced by simultaneous silencing of these two genes. These results suggest that catecholamines and NPY act conjointly to control glucoprivic feeding and that the crucial NPY/catecholamine coexpressing neurons are concentrated in the A1/C1 cell group.
Two DBH polymorphisms were investigated in 114 Brazilian alcoholics of European descent and 233 controls. Personality and life events were also analyzed among alcoholics. No significant differences were observed in allele or genotype frequencies between alcoholi
cs and controls. No association was detected between the polymorphisms and personality dimensions. Carriers of the -1021 T allele presented a higher number (F = 7.49; P = 0.007) of life events. This study provides a preliminary indication that the DBH -1021 C/T polymorphism influences the exposure to life events.
Factors interacting with core circadian clock components are essential to achieve transcriptional feedback necessary for metazoan clocks. Here, we show that all three members of the Drosophila behavior human splicing (DBHS) family of RNA-binding proteins play a
role in the mammalian circadian oscillator, abrogating or altering clock function when overexpressed or depleted in cells. Although these proteins are members of so-called nuclear paraspeckles, depletion of paraspeckles themselves via silencing of the structural noncoding RNA (ncRNA) Neat1 did not affect overall clock function, suggesting that paraspeckles are not required for DBHS-mediated circadian effects. Instead, we show that the proteins bound to circadian promoter DNA in a fashion that required the PERIOD (PER) proteins and potently repressed E-box-mediated transcription but not cytomegalovirus (CMV) promoter-mediated transcription when they were exogenously recruited. Nevertheless, mice with one or both copies of these genes deleted show only small changes in period length or clock gene expression in vivo. Data from transient transfections show that each of these proteins can either repress or activate, depending on the context. Taken together, our data suggest that all of the DBHS family members serve overlapping or redundant roles as transcriptional cofactors at circadian clock-regulated genes.
