169: Deep mutational scanning of the insulin receptor guides precision therapy for insulin resistance

️ Episode 169: Deep mutational scanning of the insulin receptor guides precision therapy for insulin resistance In this episode of PaperCast Base by Base, we explore how a comprehensive deep mutational scan of the human insulin receptor ectodomain maps the effects of ~14,000 missense variants on surface expression, insulin binding, and downstream signalling, creating a sequence–function atlas to improve diagnosis and treatment of severe insulin resistance. Study Highlights:The authors constructed a saturation mutagenesis library across residues 28–955 of INSR and used barcoded, pooled cell-based assays to quantify variant effects on receptor expression, insulin or antibody binding, and maximal AKT phosphorylation in response to insulin. Results pinpointed site 1 residues, including the αCT helix and L1 domain, as highly sensitive to mutation for insulin binding, and revealed regions where signalling is disproportionately impaired relative to binding, consistent with spare receptor behavior. The atlas showed strong concordance with known pathogenic variants and reclassified many variants of uncertain significance by linking function scores to clinical phenotypes across Donohue syndrome, Rabson–Mendenhall syndrome, and Type A insulin resistance. Importantly, the screen identified hundreds of loss‑of‑insulin‑response variants that remain selectively activatable by anti‑INSR monoclonal antibodies, nominating patients who may benefit from non‑canonical receptor agonists and highlighting distinct structural hotspots of antibody sensitivity. Conclusion:This multidimensional INSR variant map refines genetic interpretation, illuminates receptor structure–function relationships, and enables precision stratification for future antibody‑based therapies in extreme insulin resistance. Reference:Aslanzadeh V, Brierley GV, Kumar R, Çubuk H, Vigouroux C, Matreyek KA, Kudla G, Semple RK. Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance. Nature Communications. 2025;16:9143. https://doi.org/10.1038/s41467-025-64178-4 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/   On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.