A rapid in silico-to-in vivo pipeline to dissect protein-protein interactions involved in orphan diseases

Mutations in protein-coding genes may cause diseases by altering the binding to interactors. For many orphan diseases, however, the interaction partners of those proteins are unknown, and experimental mapping of protein-protein interactions is a slow, labour-intensive, and often technically challenging process. This represents a major bottleneck in deciphering pathogenic mechanisms and limits our ability to generate actionable hypotheses for therapeutic development. Our hypothesis is that combining in silico protein-protein interactions predictions with experimental in vivo validation using C. elegans mutants will sharply accelerate the elucidation of novel molecular mechanisms involved in orphan diseases. Our objective is consequently to build an integrated computational-experimental pipeline for rapid discovery and validation of protein-protein interactions relevant to orphan diseases, by combining biocomputational, genetic, biochemical, and proteomics analyses. As a proof-of-concept, we will focus on SAX-7/L1CAM, a highly conserved adhesion protein whose human ortholog is mutated in the rare neurodevelopmental CRASH syndrome. Overall, this project has the potential to broaden and accelerate the analysis of disease-relevant interaction networks, improve pathogenicity prediction, and help inform the development of tailored therapies.