Isolated Failure of Autonomic Noradrenergic Neurotransmission

Robertson, David; Goldberg, Michael R.; Onrot, Jack; Hollister, Alan S.; Wiley, R G; Thompson, John; Robertson, Rose Marie

doi:10.1056/nejm198606053142307

Cited by 167 publications

(55 citation statements)

References 21 publications

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“…NE deficiency is an autosomal recessive disorder and is quite a rare form of primary autonomic failure, which is biochemically characterized by undetectable levels of NE and epinephrine in plasma and tissues, increased levels of dopamine, and the absence of serum DBH protein (4,5). These patients clinically exhibit severe orthostatic hypotension with low blood pressure at standing and normal positions when seated.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…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.…”

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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“…Dopamine β-hydroxylase deficiency (Robertson et al, 1986) is rare autosomal recessive disorder and showed orthostatic hypotension due to deficit in autonomic regulation. Other symptoms of this disease are impaired ejaculation, ptosis, nocturia, hyper flexible joint, high palate, nasal stiffness, and so on.…”

Section: Dopamine β-Hydroxylase Deficiencymentioning

confidence: 99%

Dystonia and Dopaminergic Therapy: Rationale Derived from Pediatric Neurotransmitter Diseases

Fujioka¹

2012

Dystonia - The Many Facets

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“…Two seminal observations probably account for two basic involvements of DA in blood pressure regulations; the hypotension-inducing dopamine ␤-hydroxylase (D␤H) deficiency resulting in DA excess in humans 40 and, the hypertension-associated defective transduction of the D 1 receptor signal in renal proximal tubules with the mutant mice lacking one or both DA 1A receptor alleles. 41 Dopamine excess is thus promoting hypotension while a defect of its action contributes to hypertension.…”

Section: Experimental Evidencementioning

confidence: 99%

Peripheral dopamine in hypertension and associated conditions

Küchel

1999

J Hum Hypertens

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The purpose of this study is to review the role of dopamine in hypertension and associated conditions. The analysis of literature indicates that present knowledge is mostly based on poor markers and indirect evidence of dopaminergic activity and only few molecular biological data. Alternative markers such as plasma dopamine sulfate emerge as a possible substitute for the low plasma free dopamine detectability, one of the main obstacles in understanding the relationship between circulating dopamine and its receptor actions in hypertension. Essential hypertension represents a heterogeneous entity: based on evidence in borderline and non-modulating hypertension, the tubular dopamine receptor defect may be compensated by increased dopamine synthesis (dopamine ␤-hydroxylase suppression-mediated?) and release; alternatively, compatible with data in stable, salt-sensitive and low renin-

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Isolated Failure of Autonomic Noradrenergic Neurotransmission

Cited by 167 publications

References 21 publications

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

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

Dystonia and Dopaminergic Therapy: Rationale Derived from Pediatric Neurotransmitter Diseases

Peripheral dopamine in hypertension and associated conditions

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