A familial insulin-like growth factor-I receptor mutant leads to short stature: Clinical and biochemical characterization

Kenjiro Inagaki, Anatoly Tiulpakov, Petr Rubtsov, Polina Sverdlova, Valentina Peterkova, Shoshana Yakar, Sergei Terekhov, Derek LeRoith

Research output: Contribution to journalArticlepeer-review


Context: IGF-I/IGF-I receptor (IGF-IR) signaling pathways play important roles in longitudinal growth. A novel Arg481Glu (R481Q) mutation in IGF-IR was detected in a family with intrauterine and postnatal growth retardation. Objective: The objective of the study was to explore the mechanism whereby the R481Q mutation may be causative in growth retardation. Patients: A 13-yr-old girl with short stature was studied for functional analysis of the R481Q mutation in the IGF-IR. Results: Two members of a family who showed intrauterine and postnatal growth retardation, with increased serum IGF-I levels, demonstrated a substitution of arginine for glutamine at 481 (R481Q) in the IGF-IR. This mutation results in the formation of an altered fibronectin type III domain within the α-subunit. NIH-3T3 fibroblasts that overexpress the human wild-type or R481Q mutant IGF-IR demonstrated normal cell surface ligand binding by 125I-IGF-I binding assay. However, the fold increase of IGF-I stimulated tyrosine phosphorylation of the IGF-IR β-subunit as well as downstream activation of ERK1/2 and Akt was reduced in cells overexpressing the mutant receptor. Additionally, basal and IGF-I-stimulated levels of cell proliferation were also reduced in cells overexpressing the mutant receptor. Conclusion: Our results demonstrate that NIH-3T3 cells overexpressing a mutant form of the Igf1r gene, in which arginine at 481 is substituted by glutamine, lead to reduced levels of the fold increase of IGF-IR β-subunit phosphorylation as well as ERK1/2 and Akt phosphorylation and was accompanied by decreased cell proliferation. These results are postulated to be the cause of intrauterine and postnatal growth retardation in the described patients.

Original languageEnglish (US)
Pages (from-to)1542-1548
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


Dive into the research topics of 'A familial insulin-like growth factor-I receptor mutant leads to short stature: Clinical and biochemical characterization'. Together they form a unique fingerprint.

Cite this