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A Familial Insulin-Like Growth Factor-I Receptor Mutant Leads to Short Stature: Clinical and Biochemical Characterization

Division of Endocrinology, Diabetes, and Bone Diseases (K.I., S.Y., D.L.), Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029; Institute of Pediatric Endocrinology (A.T., V.P.), Endocrinology Research Center, Moscow 117036, Russian Federation; Engelhardt Institute of Molecular Biology (P.R., P.S.), Moscow 119991, Russian Federation; and State Research Center for Medical Genetics (S.T.), Russian Academy of Medical Sciences, Moscow 115478, Russian Federation

Address all correspondence and requests for reprints to: Derek LeRoith, Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029.

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 -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 ß-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 ß-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.

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