Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

Abstract

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.