Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.

ABSTRACT: The insulin receptor 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 variants of uncertain significance in the INSR gene, encoding the insulin receptor. By coupling saturation mutagenesis to flow-based assays, we stratified approximately 14,000 INSR extracellular missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody

SUBMITTER: Aslanzadeh V 

PROVIDER: S-EPMC12528385 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature