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Cited by 66Cardiovascular Syncope and Autonomic DisordersCardiac electrophysiology and arrhythmiasHeart Rate Variability and Autonomic Control

Familial orthostatic tachycardia due to norepinephrine transporter deficiency

ROBERTSON, DAVID, FLATTEM, NANCY, TELLIOGLU, TAHIR, CARSON, ROBERT, GARLAND, EMILY, SHANNON, JOHN R., JORDAN, JENS, JACOB, GIRIS +2 more·2001·Annals of the New York Academy of Sciences
DOI 10.1111/j.1749-6632.2001.tb03703.x
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Abstract

A bstract:Orthostatic 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 dissociataion 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.

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Crossref · 10.1111/j.1749-6632.2001.tb03703.x

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  • A loss-of-function single point mutation in the norepinephrine transporter gene SLC6A2 was identified in one family with orthostatic tachycardia.

    “A loss of function single point mutation in the NET gene SLC6A2 was identified in one family with orthostatic tachycardia”

    From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Robertson et al., 2001

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Authors
ROBERTSON, D., FLATTEM, N., TELLIOGLU, T., CARSON, R., GARLAND, E., SHANNON, J. R., JORDAN, J., JACOB, G., BLAKELY, R. D., & BIAGGIONI, I.
Affiliations
  • Vanderbilt University (US)
  • Rambam Health Care Campus (IL)
Corresponding author
ROBERTSON, DAVID
ORCID
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
2001-06
Volume
940
Issue
1
Pages
527-544
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
DOI
10.1111/j.1749-6632.2001.tb03703.x
OpenAlex
W2113285337
Cited by
64
References
85
Citations by year
2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 2 · 2014: 1 · 2013: 3 · 2012: 4
FWCI
0.55
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1699 d)
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5u01ns033460-03)
  • National Heart, Lung, and Blood Institute (P01HL056693, 5-P01-HL-56693)
  • National Institute of Neurological Disorders and Stroke (1U01-NS33460)
  • National Center for Research Resources (M01RR000095, M01-RR-00095)
Topics
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
Keywords
orthostatic intolerance, postural orthostatic tachycardia syndrome, norepinephrine transporter, plasma norepinephrine, DHPG, norepinephrine clearance, orthostatic tachycardia
MeSH terms
Amino Acid Sequence, Cardiovascular System, Carrier Proteins, Central Nervous System, Dizziness, Humans, Molecular Sequence Data, Pedigree, Posture, Tachycardia, Mutation, Missense, Symporters, Norepinephrine Plasma Membrane Transport Proteins

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