Abstract / Summary
Abstract Background Insulin signalling is mediated by the INSR -encoded receptor tyrosine kinase. Biallelic INSR variants cause the most severe insulin resistance (IR), whereas heterozygous mutations cause less rare but still severe IR. Dominantly inherited IR has been attributed to dominant negative action of intracellular (IC) missense variants, but whether extracellular (EC) variants exert dominant-negative effects, and whether simple heterozygous loss of function (LoF) causes a metabolic phenotype, remains unresolved. We aimed to clarify the phenotypic spectrum, underlying mechanisms, and natural history of IR caused by heterozygous INSR variants. Methods We aggregated genetic and clinical data from 505 individuals with monoallelic rare INSR variants from published reports, international referral centres, ClinVar/HGMD, and the Fenland population cohort. Loss-of-function (LoF) status was assigned using in silico tools including NMDetector and SpliceAI; Insulin concentrations were compared against age-, sex-, and BMI-specific reference centiles (Fenland, NHANES, IDEFICS). The common p.M1180K variant was functionally characterised by assessing cell-surface expression, and insulin-induced autophosphorylation. Results 240 probands and 265 relatives were studied. There was marked female predominance among probands (Male:Female = 1:3.4) and earlier female presentation, most often with hyperandrogenism. Presentation with diabetes, hyperinsulinaemia, or hypoglycaemia was common in both sexes. Missense variants were 14-fold enriched in the IC domain compared to gnomAD, concentrated in key functional motifs including activation and catalytic loops, whereas LoF variants were distributed in proportion to domain length. The p.M1180K variant was normally expressed but autophosphorylation-deficient. Most EC variant carriers — including genetically-ascertained individuals with EC LoF or deleterious missense variants — showed moderate to severe IR from puberty onwards. Across the whole cohort with IC or EC variants, diabetes occurred in 56% and hypoglycaemia in 55%, the latter a presenting feature in 11% of probands and common among relatives. Birthweight standard deviation score (SDS) was reduced (–1.0) and BMI SDS modestly increased (+ 0.7). Hyperandrogenism and/or Polyendocrine Metabolic Ovarian Syndrome affected 82% of postpubertal females, while GDM affected 20–53% of pregnancies. Lipid profiles were normal. Conclusions The human INSR demonstrates haploinsufficiency, with EC LoF and deleterious missense variants causing IR with variable penetrance. Hypoglycaemia is more common than previously recognised, warranting caution with diabetes therapies.