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

Vahid Aslanzadeh,Gemma V. Brierley,Rupa Kumar,Hasan Çubuk,Corinne Vigouroux,Kenneth A. Matreyek,G. Kudla,Robert K. Semple

Published 2025 in Nature Communications

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-stimulated signalling. 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 biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists. Mutations in the insulin receptor cause severe insulin resistance, but their functional impact is often unclear. Here, the authors map ~14,000 receptor variants, linking molecular defects to disease and highlighting variants responsive to therapeutic activation.

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