Аңдатпа
Background . The sodium-dependent noradrenaline transporter (NET), encoded by the SLC6A2 gene, plays a key role in the regulation of noradrenergic transmission and is associated with orthostatic intolerance, attention-deficit/hyperactivity disorder (ADHD), depression, and autonomic dysfunctions. The emergence of cryo-EM structures of human NET in complex with noradrenaline and antidepressants, along with new machine-learning algorithms, has enabled systematic in silico screening of known missense variants of the gene and the identification of previously uncharacterized pathogenic substitutions that may explain cases of idiopathic orthostatic intolerance, treatment-resistant depression, paradoxical responses to therapy, or hereditary autonomic disorders. Aim of the study was to analyze missense variants of the SLC6A2 gene registered in the NCBI database (assembly GRCh38.p14), to identify variants with the highest predicted pathogenicity scores, and to perform their structural-functional characterization using modern bioinformatics tools. Materials and methods . From 725 missense single-nucleotide variants (SNVs) of unknown clinical significance in the SLC6A2 gene (GRCh38), biallelic variants with the highest pathogenicity scores (AlphaMissense ≥0.99 and LIST-S2 ≥0.99) were selected. Two rare variants (rs1397308523 (Pro108Thr) and rs759975667 (p.Gln314Arg) underwent comprehensive in silico analysis. Results and discussion. Both substituted residues are highly conserved (ConSurf 9/9). Predictions of topology (DeepTMHMM) and domain organization (PROSITE) revealed no differences from the wild type. MutPred2 assigned overall pathogenicity scores of 0.87 and 0.91, respectively. I-Mutant 2.0 and MUpro predicted decreased protein stability (ΔΔG –1.11 and –0.94 kcal/mol). Conclusions . The variants rs1397308523 and rs759975667, which have the highest predicted pathogenicity among missense substitutions in SLC6A2, represent priority targets for functional studies and screening in clinical cohorts.