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Submitted on October 26, 2006
Accepted on January 22, 2007
Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, The Mount Sinai School of Medicine, New York, New York, The United States of America (K.I., S.Y., and D.L.), Institute of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russian Federation (A.T., V.P.), Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation (P.R., P.S.). State Research Center for Medical Genetics, Russian Academy of Medical Sciences, Moscow, Russian Federation (S.T.)
Context
IGF-1/IGF-1R signaling pathways play important roles in longitudinal growth. A novel Arg481Glu (R481Q) mutation in IGF-1R was detected in a family with intrauterine and postnatal growth retardation.
Objectives
To explore the mechanism whereby the R481Q mutation may be causative in growth retardation.
Patients
A 13 year old girl with short stature was studied for functional analysis of the R481Q mutation in the IGF-1R.
Results
Two members of a family who showed intrauterine and postnatal growth retardation, with increased serum IGF-1 levels, demonstrated a substitution of arginine for glutamine at 481 (R481Q) in the IGF-1 receptor. This mutation results in the formation of an altered fibronectin type III domain within the alpha subunit.
NIH-3T3 fibroblasts that overexpress the human wild type or R481Q mutant IGF-1R demonstrated normal cell surface ligand binding by 125I-IGF-1 binding assay. However, the fold increase of IGF-1 stimulated tyrosine phosphorylation of the IGF-1R 
-subunit as well as downstream activation of ERK1/2 and Akt were reduced in cells overexpressing the mutant receptor. Additionally, basal and IGF-1-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 igf-1r gene, in which arginine at 481 is substituted by glutamine, leads to reduced levels of the fold increase of IGF-1R -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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