Dopamine <i>β</i>-Hydroxylase Immunoreactivity in Human Cerebrospinal Fluid: Properties, Relationship to Central Noradrenergic Neuronal Activity and Variation in Parkinson's Disease and Congenital Dopamine <i>β</i>-Hydroxylase Deficiency

O’Connor, Daniel T.; Cervenka, J; Stone, Richard A.; Levine, Gail L.; Parmer, Robert J.; Franco-Bourland, Rebecca E.; Madrazo, Ignacio; Langlais, Philip J.; Robertson, David; Biaggioni, Italo

doi:10.1042/cs0860149

Cited by 49 publications

(32 citation statements)

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“…In either body fluid, enzyme activity and protein level are strongly correlated, and essentially reflect the same biochemical phenotype. [14][15][16] Thus, we refer here to D␤H enzyme activity and D␤H protein levels interchangeably as D␤H levels.…”

Section: Evidence For Genetic Influences On Vulnerability To Drug-indmentioning

confidence: 99%

A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

et al. 2000

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Low levels of dopamine ␤-hydroxylase (D␤H) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. D␤H level is a stable, genetically controlled trait. DBH, the locus encoding D␤H protein, is the major quantitative trait locus controlling plasma and CSF D␤H levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of D␤H 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*5Ј-ins/del, located approximately 3 kb 5Ј to the DBH transcriptional start site, significantly associates with plasma D␤H activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with D␤H levels, demonstrated that alleles of similar association to D␤H 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-D␤H-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 D␤H 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.Keywords: psychotic disorders; substance-related disorders; central nervous system stimulants; norepinephrine; catecholamines; schizophrenia; alleles; genes More than 60% of experienced cocaine users report paranoia during cocaine intoxication, while the remainder deny even mild cocaine-induced paranoia (CIP), despite reporting similar routes of administration, duration of cocaine dependence, and lifetime and per-binge quantities of cocaine ingested. 1-3 Satel and Edell 4 reported elevated scores on a measure of psychosis proneness in cocaine-dependent subjects who endorsed CIP compared to those who did not. These data suggest the presence of substantial interindividual variation in vulnerability to CIP. Evidence for genetic influences on vulnerability to drug-induced paranoiaSeveral lines of evidence support genetic factors as modulators of individual vulnerability to CIP. Numerous animal studies support the importance of genetic factors in behavioral responses to cocaine. 5 Abstinent human cocaine users who endorse CIP exhibit deficits in P50 sensory gating of auditory stimuli, 6 a heritable p...

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Section: Evidence For Genetic Influences On Vulnerability To Drug-indmentioning

confidence: 99%

A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

et al. 2000

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“…4, 5, and 9), cerebrospinal fluid (radioimmunoassay; see Ref. 9), and sympathetic fibers (immunocytochemistry; see Ref. 10).…”

Section: Norepinephrine (Ne)mentioning

confidence: 99%

Norepinephrine Deficiency Is Caused by Combined Abnormal mRNA Processing and Defective Protein Trafficking of Dopamine β-Hydroxylase

Kim

Leung

Huh

et al. 2011

Journal of Biological Chemistry

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Human norepinephrine (NE) deficiency (or dopamine ␤-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1؉2T3 C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1؉2T3 C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s). Norepinephrine (NE)3 is a key neurotransmitter that is synthesized in both the CNS and the peripheral nervous system and regulates many essential functions, including attention, memory, emotion, and autonomic and cardiovascular function. Like dopamine (DA) and epinephrine, NE is a catecholamine neurotransmitter and is synthesized by oxidative hydroxylation of DA catalyzed by dopamine ␤-hydroxylase (DBH). DBH is a hallmark protein of noradrenergic cells and is specifically expressed in noradrenergic neurons and chromaffin cells of the adrenal medulla. Among catecholamine-synthesizing enzymes, DBH is unique in that it is localized within large dense core vesicles (LDCV), where it exists in both soluble and membranebound forms (1). During neurotransmission, the soluble form of DBH is released into the synaptic cleft together with NE by exocytosis (2). As a result of such synaptic release, both NE and DBH are readily detectable in plasma and cerebrospinal fluid (3).NE deficiency (or DBH deficiency) is a rare congenital disorder, first described in 1986 (4, 5). Given the fundamental role of NE in CNS and peripheral nervous system functions, the report of adult patients with undetectable NE is both surprising and interesting. The report of frequent miscarriages and spontaneous abortions in mothers of known NE deficiency cases (5, 6) suggests the interesting possibility that there could be many more undiagnosed fetal and neonatal deaths resulting from NE deficiency and that those adult patients are lucky survivors. In line with this, a DBH knock-out mouse study showed less than 5% live births (7), where mortality appeared to be due to cardiovascular failure caused by NE deficiency in utero, which is reminiscent of tyrosine hydroxylase null mice (8). Pathophysiologically, NE deficiency is a severe autonomic disorder exhibiting sympathetic noradrenergic failure and adreno...

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“…In a recent genome-wide association study (GWAS), rs7040170 was identified as one of the SNPs significantly associated with plasma DβH activity ( p = 1.31×10 -14 ) (Mustapic et al, 2014). Specifically, the G allele is associated with higher plasma DβH activity and correlated with higher DβH activity in cerebrospinal fluid (CSF) (O'Connor et al, 1994). DβH is expressed early in embryonic development (Yew et al, 1995) and increases in late gestation, and may influence the cortical surface area through its roles in cell proliferation, migration and differentiation (Tiu et al, 2003).…”

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confidence: 99%

The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking

Cui

et al. 2015

NeuroImage

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The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking, NeuroImage (2015), doi: 10.1016/j.neuroimage. 2015.05.033 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 AbstractNovelty seeking (NS) is a personality trait important for adaptive functioning, but an excessive level of NS has been linked to psychiatric disorders such as ADHD and substance abuse. Previous research has investigated separately the neural and genetic bases of the NS trait, but results were mixed and neural and genetic bases have yet to be examined within the same study. In this study, we examined the interrelationships among the dopamine beta-hydroxylase (DBH) gene, brain structure, and the NS trait in 359 healthy Han Chinese subjects. We focused on the DBH gene because it encodes a key enzyme for dopamine metabolism, NS is believed to be related to the dopaminergic system and has been reported associated with DBH variation. Results showed a significant positive association between the cortical surface area of the left insula and NS score. Furthermore, the DBH genetic polymorphism at the SNP rs7040170 was strongly associated with both the surface area of the left insula and NS score, with G carriers having a larger left insula surface area and a higher NS score than AA homozygotes. Subsequent path analysis suggested that the insula partially mediated the association between the DBH gene and the NS trait. Our data provided the first evidence for the involvement of the insula in the dopamine-NS relationship.Future studies of molecular mechanisms underlying the NS personality trait and related psychiatric disorders should consider the mediation effect of the neural structure.

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Dopamine β-Hydroxylase Immunoreactivity in Human Cerebrospinal Fluid: Properties, Relationship to Central Noradrenergic Neuronal Activity and Variation in Parkinson's Disease and Congenital Dopamine β-Hydroxylase Deficiency

Cited by 49 publications

References 0 publications

A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

Norepinephrine Deficiency Is Caused by Combined Abnormal mRNA Processing and Defective Protein Trafficking of Dopamine β-Hydroxylase

The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking

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