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Structural and Functional Characteristics of the Val⁴⁴Met Insulin-Like Growth Factor I Missense Mutation: Correlation with Effects on Growth and Development

School of Molecular and Biomedical Science, University of Adelaide (A.D., K.A.M., J.C.W., B.E.F.), Adelaide 5005, Australia; Departments of Pediatrics (M.J.E.W., H.v.D., J.M.W., M.K.) and Endocrinology and Metabolic Diseases (M.K.), Leiden University Medical Center, 2300RC Leiden, The Netherlands; and Walter and Eliza Hall Institute of Medical Research (C.C.W., R.S.N.), Victoria 3050, Australia

Address all correspondence and requests for reprints to: Dr. Briony E. Forbes, University of Adelaide, Adelaide, 5005 South Australia, Australia. E-mail: briony.forbes{at}adelaide.edu.au.

We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val⁴⁴Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val⁴⁴Met IGF-I to provide a molecular basis for the phenotype observed. Val⁴⁴Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val⁴⁴Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val⁴⁴Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val⁴⁴ as an essential residue involved in the IGF-IGF-1R interaction.

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