Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation

Summary Background IGFs play key roles in intrauterine and postnatal growth through the IGF‐I receptor (IGF‐IR). We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF‐IR (R431L). Method We analysed the nucleotide sequences of the IGF1R gene of the family. We prepared R− cells (fibroblasts with targeted disruption of the IGF‐IR gene) expressing wild‐type or R431L IGF‐IR and performed functional analyses by evaluating IGF‐I binding, IGF‐I‐stimulated DNA synthesis, tyrosine phosphorylation of IGF‐IR and its substrates, and internalization by measuring [125I]IGF‐I internalization. We also performed confocal microscopy analysis. Results We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF‐IR (R431L) through an 8‐year‐old girl and her mother, both born with intrauterine growth retardation. In experiments conducted using cells homozygously transfected with the IGF‐IR R431L mutation; (i) IGF‐I binding was not affected; (ii) DNA synthesis induced by IGF‐I was decreased; (iii) IGF‐IR internalization stimulated by IGF‐I was decreased and (iv) IGF‐I‐stimulated tyrosine phosphorylation was reduced IGF‐IR by low concentrations of IGF‐I and on insulin receptor substrate (IRS)‐1 and IRS‐2. Conclusion A missense mutation (R431L) leads to the inhibition of cell proliferation, attenuation of IGF signalling and decrease in internalization of IGF‐IR. The results of this study suggest a novel link between a mutation at the IGF‐IR L2 domain and intrauterine and postnatal growth retardation.