Protein-Variant-Phenotype Study of NBAS Using AlphaFold in the Aspect of SOPH Syndrome.

NBAS gene variants cause phenotypically distinct and nonoverlapping conditions, SOPH syndrome and ILFS2. NBAS is a so-called "moonlighting" protein responsible for retrograde membrane trafficking and nonsense-mediated decay. However, its three-dimensional model and the nature of its possible interactions with other proteins have remained elusive. Here, we used AlphaFold to predict protein-protein interaction (PPI) sites and mapped them to NBAS pathogenic variants. We repeated in silico milestone studies of the NBAS protein to explain the multisystem phenotype of its variants, with particular emphasis on the SOPH variant (p.R1914H). We revealed the putative binding sites for the main interaction partners of NBAS and assessed the implications of these binding sites for the subdomain architecture of the NBAS protein. Using AlphaFold, we disclosed the far-reaching impact of NBAS variants on the development of each phenotypic trait in patients with NBAS-related pathologies.