title: Genetic basis of clinical catecholamine disorders.
abstract: Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.
authors.affiliation: Department of Pharmacology, Autonomic Dysfunction Center, Department of Medicine, Department of Neurology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Garland
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Hahn
authors.forename: Terry P
authors.initials: TP
authors.lastname: Ketch
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Keller
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: John R
authors.initials: JR
authors.lastname: Shannon
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: David
authors.initials: D
authors.lastname: Robertson
mesh_terms: D002395:Catecholamines / Q000235:genetics* / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency* / Q000235:genetics*; D005091:Exons; D006579:Heterozygote; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D009154:Mutation; D020125:Mutation, Missense; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters / Q000378:metabolism; D013577:Syndrome
chemical_list: D002395:Catecholamines; D018076:DNA, Complementary; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine