the mutation, meaning that she has one normal copy of the norepinephrine transporter gene and one copy with the mutation. Flattem also examined DNA samples from the patient's mother and nine siblings and found that the mother and four siblings (including the twin sister) were also heterozygous for the mutation.

While Flattem probed the DNA sequence, Dr. John R. Shannon, instructor of Medicine, investigated cardiovascular responses in the family members. The ones who share the transporter mutation also share characteristics of orthostatic intolerance-elevated heart rate and norepinephrine levels on standing.

Linking a genetic defect in the norepinephrine transporter to orthostatic intolerance is significant, Robertson said. "It focuses our understanding of this disorder in a new direction and shifts our attention for treatment options to entirely different kinds of drugs."

The particular transporter mutation that the researchers found was not present in any of 254 unrelated individuals, including normal controls and patients with orthostatic intolerance, indicating that it does not explain all cases of orthostatic intolerance. Robertson and Blakely believe that mutations in other regions of the transporter and in other genes will be linked to orthostatic intolerance.

"What had been speculation now clearly has a framework for looking carefully at other adrenergic (norepinephrine-related) genes in orthostatic intolerance," Blakely said.

The findings are also important as the first to connect a neurotransmitter transporter genetic defect to a clinical disease.

"We think this is the tip of an iceberg with respect to transporter defects," Blakely said. "There are a large number of candidate mutations (catalogued by geneticists) in the norepinephrine transporter gene that may be clinically relevant. And of course the norepinephrine transporter has its brothers and sisters in the gene family-like the serotonin and dopamine transpor
'"/>

Contact: Matt Scanlan
matt.scanlan@mcmail.vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
23-Feb-2000

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