Alternative titles; symbols
HGNC Approved Gene Symbol: DBH
Cytogenetic location: 9q34.2 Genomic coordinates (GRCh38): 9:133,636,363-133,659,329 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.2 | Orthostatic hypotension 1, due to DBH deficiency | 223360 | Autosomal recessive | 3 |
Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the oxidative hydroxylation of dopamine to norepinephrine. It is almost exclusively located in the adrenal medulla and the synaptic vesicles of postganglionic sympathetic neurons (summary by Kim et al., 2002).
Lamouroux et al. (1987) cloned a full-length cDNA corresponding to dopamine beta-hydroxylase from a human pheochromocytoma lambda cDNA library. The deduced 578-amino acid protein has a molecular mass of approximately 64.8 kD and is preceded by a 25-residue signal peptide that is cleaved. DBH exists in both membrane-bound and soluble forms. Taken together with the biochemical data, the observations suggested that the membrane attachment of DBH probably results from a posttranslational modification, glypiation (glycosylphosphatidylinositolation) being the most likely candidate. Comparative amino acid sequence analysis showed no homology with other catecholamine synthesizing enzymes.
Kobayashi et al. (1989) isolated 2 DBH mRNA transcripts: 2.7-kb type A and 2.4-kb type B. The transcripts differed by 300 bp in length and had the same amino acid sequence except for the 3-prime, untranslated region. The findings indicated that alternative use of 2 polyadenylation sites from a single DBH gene generates different mRNA types.
Kobayashi et al. (1989) determined that the DBH gene has 12 exons and spans 23 kb. Exon 12 encodes the 3-prime-terminal region of 1,013 bp of the type A mRNA, including the 300 bp sequence.
By in situ hybridization, Craig et al. (1988) mapped the DBH gene to chromosome 9q34.
Pilz et al. (1992) used interspecies backcrosses to map the mouse Dbh gene to mouse chromosome 2.
Joh et al. (1983, 1984) suggested that 3 enzymes of the pathway of catecholamine synthesis, DBH, phenylethanolamine N-methyltransferase (PNMT; 171190), and tyrosine hydroxylase (TH; 191290), may be encoded by a single gene or by linked genes derived from a common ancestor. The theory was based on the following observations: (1) proteolytic digestion of these enzymes produces similar peptides whose amino acid composition is nearly identical; (2) antibodies to each enzyme coprecipitate more than 1 of the 3 enzymes from in vitro poly(A)mRNA translation products; (3) DBH cDNA clones cross-hybridize with PNMT mRNA, and PNMT cDNA cross-hybridizes with DBH mRNA, and (4) DBH and PNMT cDNA probes hybridize to several common restriction fragments of total cellular DNA.
Orthostatic Hypotension 1
In 2 unrelated patients with orthostatic hypotension-1 (ORTHYP1; 223360) reported by Robertson et al. (1986) and Biaggioni et al. (1990), Kim et al. (2002) identified compound heterozygosity for mutations in the DBH gene (609312.0002-609312.0004).
Other Disease Associations
Plasma DBH activity varies widely between individuals, and a subgroup of the population has very low activity levels. By use of both sequencing-based mutation analysis of extreme phenotypes and genotype-phenotype correlations in samples from African Americans, European Americans, and Japanese, Zabetian et al. (2001) identified a novel polymorphism (-1021C-T; 609312.0001) in the 5-prime flanking region of the DBH gene that accounts for 35 to 52% of the variation in plasma DBH activity in these populations. In European Americans, homozygosity at the T allele predicted the very low DBH activity trait, and activity values in heterozygotes formed an intermediate distribution, indicating codominant inheritance.
Associations Pending Confirmation
In a study of 284 individuals from 70 European American pedigrees multiplex for schizophrenia (181500), Cubells et al. (2011) used linkage analysis with markers on chromosome 9 to confirm an association between plasma DBH activity and SNPs within the DBH gene (maximum multipoint lod score of 6.33 at position 2.8 cM proximal to the DBH gene). Accounting for the contributions to the linkage signal of 3 SNPs at DBH, rs1611115 (609312.0001), rs1611122, and rs6271, reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Genomewide SNP analysis provided evidence for linkage to markers at chromosome 20p12 (multipoint lod of 3.1 at 27.2 cM). There was no evidence to support linkage of this trait to chromosome 19. Cubells et al. (2011) reviewed previous studies showing an association between variation in plasma levels of DBH activity and expression of psychotic symptoms, and hypothesized that variation in DBH may be a genetic modifier of psychotic symptoms in psychiatric disorders.
McKinney et al. (2000) found that allelic variations in the DBH and monoamine oxidase (MAOA; 309850) genes predicted whether a person was a heavy smoker and how many cigarettes they consumed. More heavy smokers had the DBH 1368A allele when compared to light smokers; conversely, heavy smokers were less likely to have the MAOA 1460C allele. The results supported the view that these enzymes help to determine a smoker's requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some find it very difficult to stop smoking.
Lea et al. (2000) tested polymorphisms within the DBH gene as well as within the serotonin transporter (SERT; 182138) and dopamine receptor (DRD2; 126450) genes in 177 unrelated Caucasian subjects with migraine and 182 controls. In addition, an independent sample of 82 families affected with migraine was examined. A DBH intragenic dinucleotide polymorphism showed altered allelic distribution between migraine and control groups. The transmission/disequilibrium test, which was implemented on the family data, indicated distortion of allele transmission for the same DBH marker. These results provided evidence for allelic association of the DBH gene with typical migraine susceptibility (157300).
Exclusion Studies
By linkage analysis, Schuback et al. (1991) excluded the DBH gene as the site of the mutation in several forms of torsion dystonia (128100, 224500) and in myoclonic dystonia (159900).
Thomas et al. (1995) used gene targeting to produce mice that lack Dbh and are therefore unable to synthesize noradrenaline or adrenaline. They found that in heterozygous mothers, most homozygous embryos died in utero and only about 5% reached adulthood. Survival probably depended on catecholamine transfer across the placenta, because in homozygous mothers all embryos died in utero. Mortality was due to lack of noradrenaline in utero because it could be prevented by treatment with dihydroxyphenylserine (DOPS), a precursor that can be converted to noradrenaline in the absence of DBH. Mutant embryos had a histologic phenotype similar to that of embryos deficient in tyrosine hydroxylase, suggesting that death might be due to cardiovascular failure, as was probably the case with TH-deficient embryos. Thomas and Palmiter (1997) found impaired maternal behavior in these mice with targeted disruption of the Dbh gene. Most heterozygous pups born to Dbh -/- females died within several days of birth and were often found scattered within the bedding. Potential causes, including deficits in olfaction and lactation, were not apparent. A deficit in maternal behavior was confirmed by the lack of pup retrieval exhibited by Dbh -/- virgin females. Restoration of norepinephrine shortly before but not after birth induced females that had previously abandoned their litters to act maternally. These results suggested to the authors that norepinephrine is responsible for long-lasting changes that promote maternal behavior during both development and parturition in mice.
Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose occurs in response to cold and overeating, and there is an inverse relationship between diet-induced thermogenesis and obesity in both humans and animal models. As a potential model for obesity, Thomas and Palmiter (1997) generated mice that could not synthesize noradrenaline or adrenaline by inactivating the gene that encodes Dbh. These mice were cold intolerant because they had impaired peripheral vasoconstriction and were unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP; 113730). The mutants had increased food intake but did not become obese because their basal metabolic rate (BMR) was also elevated. The unexpected increase in BMR was not due to hyperthyroidism, compensation by the widely expressed UCP2 (601693), or shivering.
Weinshenker et al. (2002) took a genetic approach to study how norepinephrine signaling modulates psychostimulant responses by testing locomotor response to amphetamine in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack norepinephrine. Surprisingly, these null animals were hypersensitive to the behavioral effects of amphetamine. The agent elicited greater locomotor activity in the null mice compared to controls. Weinshenker et al. (2002) noted the observation that cocaine abusers with low-activity DBH haplotypes have increased sensitivity to cocaine-induced paranoia and euphoria (Cubells et al., 2000), suggesting that DBH enzyme levels modulate both dysphoric and rewarding effects of psychostimulants in humans.
It had been hypothesized that the adrenergic nervous system mediates enhanced memory consolidation of emotional events. Murchison et al. (2004) tested this hypothesis in several learning tasks using mutant mice conditionally lacking norepinephrine and epinephrine (Dbh -/-), as well as control mice and rats treated with adrenergic receptor agonists and antagonists. Adrenergic signaling was critical for the retrieval of intermediate-term contextual and spatial memories, but was not necessary for the retrieval or consolidation of emotional memories. The role of norepinephrine in retrieval required signaling through the beta-1 adrenergic receptor in the hippocampus. The results demonstrated that mechanisms of memory retrieval can vary over time and can be different from those required for acquisition or consolidation. Murchison et al. (2004) concluded that these findings may be relevant to symptoms in several neuropsychiatric disorders as well as the treatment of cardiac failure with beta-blockers.
Using the tail-suspension test, Cryan et al. (2004) found that, compared to wildtype mice, Dbh-null mice had reduced sensitivity to several antidepressants, including the norepinephrine reuptake inhibitors desipramine and reboxetine and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine. Reinstitution of norepinephrine in Dbh-null mice reinstated the behavioral effects, demonstrating that the reduced sensitivity was due to decreased norephinephrine function. Cryan et al. (2004) suggested that norepinephrine plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including SSRIs.
In mice lacking Dbh, an enzyme critical for norepinephrine synthesis, Olson et al. (2006) found that norepinephrine was necessary for morphine-induced conditioned place preference (a measure of reward) and locomotion. These deficits were rescued by systemic norepinephrine restoration. Viral restoration of Dbh expression in the nucleus tractus solitarius, but not in the locus ceruleus, restored conditioned place preference for morphine. Morphine-induced locomotion was partially restored by Dbh expression in either brain region. Olson et al. (2006) concluded that norepinephrine signaling by the nucleus tractus solitarius is necessary for morphine reward.
Using an in silico search, followed by PCR, Hejjas et al. (2007) identified variable number of tandem repeat polymorphisms in genes of the dopaminergic system in 4 dog breeds and European gray wolves. Polymorphisms of the DRD4 (126452), DBH, and DAT (SLC6A3; 126455) genes were associated with attention deficit, but not activity-impulsivity, in Belgian Tervuerens, a breed that had almost all genetic variants identified.
This polymorphism (rs1611115) was originally reported as a -1021C-T transition (Zabetian et al., 2001), but is now referred to as -970C-T (Cubells et al., 2011).
Zabetian et al. (2001) found that a C-to-T polymorphism at nucleotide -1021 in the 5-prime region of the DBH gene was related to dopamine beta-hydroxylase activity levels in plasma. In a study of 174 European Americans, 16 of TT genotype had DBH activity of 4.1; 46 of CT genotype had DBH activity of 25.2; and 112 of CC genotype had DBH activity of 48.1 nmol/min/ml.
In 809 patients with Parkinson disease (168600), Healy et al. (2004) found underrepresentation of the DBH T/T genotype and the T allele compared to controls, suggesting a protective effect of the T allele against the development of PD. Higher serum dopamine levels occurred in individuals with lower DBH activity, corresponding to the T allele. Although no DBH cDNA was amplified from a substantia nigra cDNA library, indicating an absence of protein expression in the substantia nigra, Healy et al. (2004) suggested that individuals with the low DBH-expressing allele may have higher endogenous dopamine in neurons of the locus ceruleus or elsewhere in the basal ganglia. All 19 chimpanzees tested were homozygous for the C allele, suggesting that the T allele arose in the evolutionary tree between humans and chimpanzees. However, Chun et al. (2007) found that the -1021C-T polymorphism did not modify disease risk or age at onset of Parkinson disease in a comparison of 1,244 patients and 1,186 controls of self-defined European American ancestry.
Among 675 patients with various forms of epilepsy and over 1,000 control individuals, Depondt et al. (2004) found no association between the -1021C-T polymorphism and susceptibility to epilepsy or response to antiepileptic medication.
In 2 unrelated patients with orthostatic hypotension-1 (ORTHYP1; 223360), Kim et al. (2002) identified a heterozygous T-to-C transition in the donor splice site of exon 1 of the DBH gene. Each patient was compound heterozygous for another DBH mutation (609312.0003 and 609312.0004, respectively). Functional analysis showed that the mutation resulted in aberrant splicing, although some proper splicing was observed. Kim et al. (2002) noted that the haplotype containing the splice site mutation in both patients also had the -1021C-T change (609312.0001), which had been associated with low plasma DBH, and postulated that the 2 variants together result in DBH protein deficiency. Among 88 healthy unrelated European Americans, the IVS1+2T-C transition had a minor allele frequency of 0.011.
In a revised analysis including 801 unrelated adults of African American, European American, and German origin and 260 African American mothers and infants, Zabetian et al. (2003) determined that the frequency of the IVS1+2T-C transition was 0.001. One African American preterm infant was heterozygous for the mutation. Haplotype analysis of the African American infant and the 2 European American patients reported by Kim et al. (2002) showed that the T-to-C transition arose from a common mutational event.
In a patient with orthostatic hypotension-1 (ORTHYP1; 223360), Kim et al. (2002) identified compound heterozygosity for 2 mutations in the DBH gene: one allele had a 300C-A transversion in exon 2, resulting in an asp100-to-glu (D100E) substitution in a highly conserved region; the second allele contained a splice site mutation (609312.0002). Each of the patient's parents was heterozygous for 1 of the mutations, and the D100E mutation was not identified in 88 control individuals.
In a patient with orthostatic hypotension-1 (ORTHYP1; 223360), Kim et al. (2002) identified compound heterozygosity for mutations in both alleles of the DBH gene: one allele, inherited from the mother, contained a 259G-A transition in exon 1, resulting in a val87-to-met (V87M) substitution, and a 991G-A transition in exon 6, resulting in an asp331-to-asn (D331N) substitution in cis; the other allele, inherited from the father, had a splice site mutation (609312.0002). Species comparison showed that residue 331 is highly conserved.
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