Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R

J Clin Endocrinol Metab. 2006 Jun;91(6):2264-71. doi: 10.1210/jc.2005-2146. Epub 2006 Mar 28.


Context: Signaling via the IGF-I receptor (IGF-IR) is crucial for normal prenatal and postnatal growth. The heterozygous IGF-IR mutation Arg59Ter resulted in reduced IGF-IR expression and represents haploinsufficiency of the human IGF1R gene.

Objective: We studied clinical and in vitro aspects of a human IGF1R gene dosage effect. We provide detailed clinical data on the two half-brothers and their mother with the Arg59Ter mutation. Arg59Ter and control fibroblasts were examined for functionality of IGF-I and insulin-stimulated receptor phosphorylation and signal transduction.

Results: The two brothers presented with primary microcephaly, mild mental retardation, and intrauterine as well as postnatal growth deficits. After GH therapy (30 microg/kg.d) for 24 months, the growth deficit in the propositus decreased by +1.0 sd. There was no clinical evidence for impaired glucose tolerance or hypoglycemia in all Arg59Ter subjects. In vitro, IGF-IR-deficient Arg59Ter cells expressed less IGF-IR and unchanged insulin receptor (IR) protein. Receptor autophosphorylation and phosphorylation of downstream protein kinase B/Akt exhibited resistance to IGF-I but showed an augmented response to insulin in Arg59Ter cells. Decreased IGF-IR content was accompanied by a reduction of IGF-IR/IR receptor hybrids, and therefore, increased levels of IR/IR homodimers probably explain increased insulin-stimulated receptor autophosphorylation and Akt phosphorylation.

Conclusions: In vivo and in vitro IGF-I resistance in Arg59Ter subjects and fibroblasts indicates a human IGF1R gene dosage effect involving not only the IGF-IR, but also IGF-IR/IR hybrids. The abundance of both the IGF-IR protein and IGF-IR/IR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Weight
  • Female
  • Gene Dosage*
  • Glucose / metabolism
  • Growth Hormone / therapeutic use
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Male
  • Mutation*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / genetics*


  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Glucose