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Familial orthostatic tachycardia due to norepinephrine transporter deficiencyOrthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.
Document ID
20040112360
Document Type
Reprint (Version printed in journal)
Authors
Robertson, D.
(Vanderbilt University Nashville, TN 37232-2195, United States)
Flattem, N.
Tellioglu, T.
Carson, R.
Garland, E.
Shannon, J. R.
Jordan, J.
Jacob, G.
Blakely, R. D.
Biaggioni, I.
Date Acquired
August 21, 2013
Publication Date
June 1, 2001
Publication Information
Publication: Annals of the New York Academy of Sciences
Volume: 940
ISSN: 0077-8923
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: M01 RR00095
CONTRACT_GRANT: 5P01 HL56693
CONTRACT_GRANT: 1U01NS33460
Distribution Limits
Public
Copyright
Other
Keywords
Review, Tutorial
NASA Discipline Regulatory Physiology
Review
Non-NASA Center

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