Familial Orthostatic Tachycardia Due to Norepinephrine Transporter Deficiency

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 typ...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2001-06, Vol.940 (1), p.527-544
Main Authors: ROBERTSON, DAVID, FLATTEM, NANCY, TELLIOGLU, TAHIR, CARSON, ROBERT, GARLAND, EMILY, SHANNON, JOHN R., JORDAN, JENS, JACOB, GIRIS, BLAKELY, RANDY D., BIAGGIONI, ITALO
Format: Article
Language:English
Subjects:
Amino Acid Sequence - genetics
Cardiovascular System - physiopathology
Carrier Proteins - genetics
Central Nervous System - physiopathology
Dizziness - etiology
Dizziness - genetics
Dizziness - physiopathology
Humans
Life Sciences (General)
Mitral valve prolapse
Molecular Sequence Data
Mutation, Missense - physiology
Norepinephrine
Norepinephrine Plasma Membrane Transport Proteins
Norepinephrine transporter (NET)
Orthostatic intolerance (OI)
Pedigree
Posture
Space life sciences
Symporters
Tachycardia
Tachycardia - etiology
Tachycardia - genetics
Tachycardia - physiopathology
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Summary: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 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.
ISSN:0077-8923
1749-6632
DOI:10.1111/j.1749-6632.2001.tb03703.x