Summary
The insulin receptor (INSR) entrains tissue growth and metabolism to nutritional conditions. Complete loss of function in humans leads to extreme insulin resistance and infantile mortality, while loss of 80-90% function permits longevity of decades. Even low-level activation of severely compromised receptors, for example by anti-receptor monoclonal antibodies, thus offers the potential for decisive clinical benefit. A barrier to genetic diagnosis and translational research is the increasing identification of INSR variants of uncertain significance. We employed saturation mutagenesis coupled to multidimensional flow-based assays to stratify approximately 14,000 INSR extracellular domain missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody-stimulated signaling. The resulting function scores correlate strongly with clinical syndromes, offer insights into dynamics of insulin binding, and reveal novel potential gain-of-function variants. This INSR sequence-function map has high biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists.
Competing Interest Statement
RKS has received consulting fees from Novartis, Astra Zeneca, and Alnylam, research contribution in kind from Pfizer, and speaking fees from Novo Nordisk, Eli Lilly, and Amryt. CV serves as investigator in the APL-22 clinical study sponsored by Chiesi Farmaceutici and in the REGN4461-PLD-20100 sponsored by Regeneron Pharmaceuticals, and has served as speaker and received support for attending meetings from Amryt Pharmaceuticals (now Chiesi Farmaceutici) and Sanofi.
