A Heterozygous Mutation of the Insulin-Like Growth factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

J Clin Endocrinol Metab. 2010 May;95(5):2316-24. doi: 10.1210/jc.2009-2404. Epub 2010 Mar 31.


Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders.

Objective: Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation.

Patient: At birth, the girl's length was 47 cm [-1.82 sd score (SDS)], and her weight was 2250 g (-2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS).

Results: Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum.

Conclusion: The V599E-IGF1R mutation interferes with the receptor's trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient's wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Birth Weight
  • Body Size
  • Cognition Disorders / genetics
  • Endoplasmic Reticulum / metabolism*
  • Exons / genetics
  • Female
  • Fetal Growth Retardation / genetics*
  • Glutamic Acid / genetics
  • Growth Disorders / genetics*
  • Heterozygote*
  • Humans
  • Infant, Newborn
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Intellectual Disability / genetics
  • Microcephaly / genetics
  • Mutation, Missense*
  • Polymerase Chain Reaction
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Valine / genetics


  • Insulin-Like Growth Factor Binding Protein 3
  • Glutamic Acid
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Valine