Disease relevance of DBH

• In the adrenal pheochromocytoma both DBH- and PNMT-positive cells were seen, whereas the two extra-adrenal tumors contained only DBH [1].
• One angiomyolipoma showed allele loss for the markers ABO, DBH and D9S66, but not for D9S149 or D9S67 [2].
• METHODS: Paraffin-embedded tumor specimens from 21 midgut carcinoid patients and 20 pheochromocytoma patients (10 sporadic and 10 MEN type IIa-related tumors) were stained for TH, DBH, and PNMT, using a three-step biotin-avidin-peroxidase method [3].
• By immunocytochemistry, NPY-immunoreactive (-IR) principal ganglion cells in sympathetic ganglia and the pelvic plexus were also found to contain dopamine-beta-hydroxylase (DBH) and tyrosine hydroxylase (TH), strongly suggesting that the NPY-IR cells are noradrenergic [4].
• Superior cervical ganglia from 7 human cadavers (3-7 h post mortem) were immunostained for tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and 14 different neuropeptides [5].

Psychiatry related information on DBH

• Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects [6].
• Low DBH levels correlate indirectly with the seriousness of the hyperkinetic syndrome in children [19,20] [7].
• Measurements of dopamine-beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase (MAO) along with 27 polymorphic marker phenotypes were available for 162 patients with major affective disorders and 1,125 of their relatives [8].
• They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group [9].
• In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation [10].

High impact information on DBH

• In DBH-NGF mice, the sympathetic trunk and nerves growing to peripheral tissues were enlarged and contained an increased number of sympathetic fibers [11].
• Comparative amino acid sequence analysis establishes that DBH shares no homology with the other catecholamine synthesizing enzymes, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase [12].
• A full length dopamine-beta-hydroxylase (DBH) cDNA clone was isolated from a human pheochromocytoma lambda gt11 library [12].
• Taken together with available biochemical data, these observations suggest that the membrane attachment of DBH probably results from a post-translational modification, glypiation being the most likely candidate [12].
• Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 30 schizophrenic patients and 27 normal controls [13].

Chemical compound and disease context of DBH

• Recent findings of an association between human NE deficiency and variants at the dopamine beta-hydroxylase (DBH) gene [Kim et al., 2002] prompted us to investigate these markers in patients with autonomic disorders; 38 with orthostatic intolerance (OI), 26 with pure autonomic failure (PAF), and 39 with multiple system atrophy (MSA) [14].
• We investigated the effect of long term treatment with nicotine on TH and DBH gene expression in rat PC12 pheochromocytoma cells [15].
• The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children [9].
• A twin study on three enzymes (DBH, COMT, MAO) of catecholamine metabolism. Correlations with MMPI [16].
• In patients with tardive dyskinesia (TD), cerebrospinal fluid DA, DOPAC, HVA, NA, and serum DBH were distributed into three factors; in patients without TD, these substances were assembled in only one factor [17].

Biological context of DBH

• Ovarian neurons were identified as a site of TH and DBH gene expression, and surprisingly, oocytes were identified as an exclusive site of DBH synthesis [18].
• The absence of DBH from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype [19].
• Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2.63) and with D16S291 on chromosome 16 (max lod 3.98) at values of theta of 0.2 in each case [20].
• In addition, we have isolated and mapped the 3' portions of three putative genes located within or immediately distal to the DBH gene, including one large gene that runs on the opposite strand to DBH and utilizes portions of two DBH exons [21].
• Physical and cDNA mapping in the DBH region of human chromosome 9q34 [21].

Anatomical context of DBH

• In the normal adrenal medulla more DBH- than PNMT-immunoreactive gland cells were observed [1].
• The physiological relevance of this transporter system and DBH in oocytes was indicated by the ability of isolated oocytes to metabolize exogenous DA into NE [18].
• Although many neuroendocrine tissues outside of the adrenal gland contained immunoreactive NE, only a small percentage of these tissues contained DBH [22].
• DBH immunoreactivity labeled primarily the noradrenergic pontic cell groups and, to a lesser extent, groups located in the medulla oblongata [23].
• DBH-like immunoreactivity (IR) was probably labeling the noradrenergic (NA) fibers and terminals in the cerebral cortex since no PNMT-IR fibers were detected [24].

Associations of DBH with chemical compounds

• This paper summarizes the most important genetic data in correlations with biochemical periphery parameters (especially for DBH, HVA, MHPG, serotonin) [25].
• Likewise, the inhibition of native and recombinant human DBH by fusaric acid and SKF102698 is not significantly different but IC50 values are 2-3-fold higher than that for the bovine enzyme [26].
• The Km of tyramine for native and recombinant human enzymes are virtually the same but higher than bovine DBH by about 3-fold [26].
• Two variants of human DBH that differ by a single amino acid (either serine or alanine) at position 304 were expressed in Drosophila cells, purified, and found to have no significant difference in enzyme activity [26].
• Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH [27].

Physical interactions of DBH

• In addition, alteration of the YY1-binding site decreased TPA-mediated induction of the DBH promoter activity, suggesting that contiguous cis-regulatory element(s) cooperate with this novel sequence motif [28].

Regulatory relationships of DBH

• We have evaluated whether post-translational modification of Arix regulates PKA-mediated DBH gene transcription [29].
• Strikingly, the YY1 element positively regulated basal DBH transcription while simultaneously regulating cAMP-mediated induction negatively, which is a novel mechanism of promoter function [30].
• Furthermore, SI and SIII preferentially repressed the heterologous thymidine kinase and homologous DBH proximal promoter activities in nonneuronal cells [31].
• Furthermore, expression of RE1-silencing transcription factor/neuron-restrictive silencer factor repressed neither DBH nor tyrosine hydroxylase promoter activity [31].
• Using transient transfection of P19 or NT-2 cells, HAND2 is shown to synergistically enhance Phox2a-driven transcriptional activity at the DBH promoter, an effect that is enhanced by cAMP [32].

Other interactions of DBH

• We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH [33].
• Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR(DAT1)=1.29 (1.04-1.59), RR(DBH)=1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR=1.59 (1.05-2.42) [34].
• RESULTS: TH was demonstrated in 9 (43%) of 21 carcinoids and in all (100%) of 20 pheochromocytomas, DBH in 8 (38%) carcinoids and in 15 (75%) pheochromocytomas, and PNMT in 7 (33%) carcinoids and in 13 (65%) pheochromocytomas [3].
• Serial sections were immunohistochemically stained for DBH and hybridized with rabbit-specific TH and NET cRNAs and a human NPY probe [35].
• AADC and DBH were present universally in all functioning and non-functioning tumours, including TH-negative tumours [36].

Analytical, diagnostic and therapeutic context of DBH

• Therefore, we utilized the sensitive in situ hybridization technique to identify the presence of these messages in conjunction with the location of NE cells, the latter being marked by dopamine beta-hydroxylase (DBH), the specific enzyme for NE synthesis [35].
• Double-labelling experiments using TH and DBH, and surgical sympathectomy revealed that the majority of NPY-IR fibres around blood vessels were probably noradrenergic [37].
• Further the enzyme activities of CA biosynthesis in human vas deferens excised at elective vasectomy were related with the blood pressure, plasma CA, serum DBH of 57 men at the time of vasectomy [38].
• We have purified native and recombinant human DBH by a modified purification procedure using SP-Sepharose, lentil lectin-Sepharose and gel-filtration chromatography and carried out studies to compare the two enzymes [26].
• These results strongly support the conclusion that recombinant human DBH from Drosophila S2 cells can be used in place of human neuroblastoma-derived DBH for drug screening, characterization of the enzyme's physicochemical properties, and determination of structure-function relationships [26].

References