ArticleNature communications2025
Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- sortscore: Sort-seq MAVE scoring and visualization using Python.Bioinformatics (Oxford, England) · 2026Article
- Family with two novelClinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2026Article
- Comprehensive assessment of the genotype-phenotype spectrum and treatment for monoallelic insulin receptoropathy in a cohort of 505 people.Research square · 2026Article
- Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.The Journal of clinical endocrinology and metabolism · 2026Observational
- VEFill: accurate and generalizable deep mutational scanning score imputation across protein domains.Molecular systems biology · 2026Article
- Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance.bioRxiv : the preprint server for biology · 2026Article
- Massively parallel functional genomic assays in endocrinology: from promise to delivery.Journal of molecular endocrinology · 2026Review
- The genetic architecture of an allosteric hormone receptor.Nature communications · 2026Article
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 2026Article
- The evolving landscape of pharmacogenomics: Current achievements and future directions.Pharmacological reviews · 2026Review
- Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.Nature communications · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.Nature structural & molecular biology · 2025Article
- Multiplex, multimodal mapping of variant effects in secreted proteins.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
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.
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