Evaluation of single nucleotide polymorphisms in the human norepinephrine transporter (hNET) gene for structural, functional, and pathogenic significance.

The norepinephrine transporter (NET) is a key regulator of noradrenergic neurotransmission and homeostasis, regulating the norepinephrine levels in the brain and peripheral tissues. hNET is a major target in neuropsychiatric disorders such as major depressive disorder, autonomic dysfunction, and attention deficit hyperactivity disorder (ADHD). The human norepinephrine transporter gene (, ) contains 504 missense single nucleotide polymorphisms (SNPs). These SNPs have been identified in public databases. Elucidating the molecular effects of missense SNPs on hNET protein function and structure may provide insight into how hNET missense SNPs affect the biological activity of the protein and contribute to the etiopathogenesis of disease. Therefore, in our study, we aimed to analyze the structural, functional, and pathogenic effects of genetic variants in the human gene using various bioinformatics tools. In our study, rs45564432 (T283R), rs121918126 (A457P), rs5558 (F528C), rs5566 (A369P), rs13306041 (R121Q), rs147833183 (R301H), rs201263363 (Y294H), rs201586185 (A369V), and rs373891109 (T258I) variants have been identified as pathogenic with structural and functional effects. Our results demonstrated the significance of high-risk missense SNPs on the function and structure of the transporter protein. We anticipate that the results of this study will contribute to future experimental studies investigating the relationship between genetic variants and the pathogenesis and treatment of neuropsychiatric disorders.