Study on IGF-I insensitivity: Function and phenotype of mutated IGF-I receptor gene

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Context: Insulin-like growth factor (IGF-I) plays key roles in intrauterine fetal growth as well as postnatal growth via IGF-I receptor (IGF-IR). Recently, IGF-IR gene mutations have been reported in four patients with short stature born intrauterine growth retardation (IUGR).Subjects and Methods: We analyzed the nucleotide sequences of IGF-IR gene in 29 patients with IUGR short stature. Mutated IGF-IR gene was transfected in 3T3-like mouse embryo cells with a targeted disruption of the IGF-IR genes (R-cells). Functions of mutated IGF-IR in transfected R-cells were evaluated by IGF-I binding, IGF-I stimulated DNA synthesis and ss-subunit autophosphorylation and internalization analysis.Results: 1) A new heterozygous missense mutation at L2 domain of IGF-IR (R431L) was identified in a 6-year-old Japanese girl with IUGR short stature and her mother. 2) DNA synthesis induced by IGF-I was significantly decreased in R-cells transfected with mutated IGF-IR. 3) IRS-2 phosphorylation in response to IGF-I was decreased in R-cells transfected with mutated IGF-IR. 4) Internalization was decreased in R-cells transfected with mutated IGF-IR.Conclusion: A missense mutation (R431L) causes decreased IGF action by decreased internalization of IGF-IR, and results in growth retardation. The results of this study provide new important information on IUGR short stature with IGF-IR mutation and a role of L2 domain of IGF-IR.