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Genetic basis of clinical catecholamine disordersNorepinephrine 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.
Document ID
20040087990
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Garland, Emily M.
(Vanderbilt University Nashville, Tennessee 37232, United States)
Hahn, Maureen K.
Ketch, Terry P.
Keller, Nancy R.
Kim, Chun-Hyung
Kim, Kwang-Soo
Biaggioni, Italo
Shannon, John R.
Blakely, Randy D.
Robertson, David
Date Acquired
August 21, 2013
Publication Date
October 1, 2002
Publication Information
Publication: Annals of the New York Academy of Sciences
Volume: 971
ISSN: 0077-8923
Subject Category
Life Sciences (General)
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
Review
Case Reports
Review, Tutorial
NASA Discipline Regulatory Physiology

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