Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants

Diabetes. 2021 Aug;70(8):1874-1884. doi: 10.2337/db20-1145. Epub 2021 Jun 1.


We previously reported genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of IGF1R, which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Body Height / genetics*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Genetic Association Studies
  • Growth Disorders / genetics*
  • Humans
  • Insulin Resistance / genetics
  • Mutation, Missense
  • Phenotype
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism
  • Retrospective Studies


  • Antigens, CD
  • IGF1R protein, human
  • INSR protein, human
  • Receptor, IGF Type 1
  • Receptor, Insulin

Associated data

  • figshare/10.2337/figshare.14579415