Our understanding of orthostatic intolerance was greatly expanded in 2000 when norepinephrine transporter (NET) deficiency was reported. In a proband with significant orthostatic symptoms and tachycardia, we found:
Studies of NET gene structure in the proband revealed a coding mutation which 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. Studies of the proband and her family revealed correlations of plasma NE, DHPG/NE, and heart rate with the mutant allele. 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.