Protein-Variant-Phenotype study of NBAS in the context of nonsense-mediated RNA decay proteins using AlphaFold

Abstract

Pathogenic variants in the NBAS cause multisystem disorders, including SOPH syndrome and ILFS2. NBAS performs multiple cellular functions, which may explain the complexity of its clinical manifestations. Previously, we developed the Protein-Variant-Phenotype (PVP) approach using AlphaFold to analyze binding sites and their impact on phenotype. In this study, we used AlphaFold3 to investigate NBAS interactions with SMG proteins of the NMD complex to explore the potential contribution of disrupted protein interactions to the multisystem phenotype. We identified consensus binding sites between NBAS and SMG9 in the C-terminal region, which is associated with optic nerve atrophy. These findings suggest an alternative mechanism for NBAS involvement in NMD through auxiliary SMG proteins. Furthermore, this study is the first to associate C-terminal of NBAS with a specific phenotypic trait and cellular mechanism, providing a foundation for potential therapeutic approaches.