Partial Primary Deficiency of Insulin-Like Growth Factor (IGF)-I Activity Associated with IGF1 Mutation Demonstrates Its Critical Role in Growth and Brain Development

• Published in: The journal of clinical endocrinology and metabolism Vol. 94; no. 10; pp. 3913 - 3921
• Main Authors: Netchine, Irène, Azzi, Salah, Houang, Muriel, Seurin, Danielle, Perin, Laurence, Ricort, Jean-Marc, Daubas, Claudine, Legay, Christine, Mester, Jan, Herich, Robert, Godeau, François, Le Bouc, Yves
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.10.2009; Endocrine Society
• Subjects: Arginine; Biological and medical sciences; Brain - growth & development; Brain - metabolism; Cell Proliferation; Child; DNA Mutational Analysis; DNA, Complementary - analysis; Endocrinopathies; Feeding. Feeding behavior; Female; Fetuses; Fundamental and applied biological sciences. Psychology; Gestational age; Glutamine; Growth hormones; Humans; Igf1 gene; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-like growth factor I; Insulin-Like Growth Factor I - deficiency; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor I receptors; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Male; Medical sciences; Mutation; Mutation, Missense; Pedigree; Peptides; Phenotypes; Phosphorylation; Postpartum period; Serum levels; Small for gestational age; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Brain; Obesity; Nutrition; Growth; Deficiency; Central nervous system; Nutrition disorder; Metabolic diseases; Insulin like growth factor 1; Biological activity; Encephalon; Insulin like growth factor; Association; Partial; Primary; Genetics; Mutation; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2009-0452

Context: IGF-I is essential for fetal and postnatal development. Only three IGF1 defects leading to dramatic loss of binding to its type 1 receptor, IGF-1R, have been reported. Patient: We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene. Result: We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient’s IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay. Conclusion: This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use.IGF-I mild deficiency due to a novel homozygous mutation demonstrates that the integrity of IGF-I binding to its receptor is crucial for growth and brain development.