A Variable Degree of Intrauterine and Postnatal Growth Retardation in a Family with a Missense Mutation in the Insulin-Like Growth Factor I Receptor

Context: The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding of IGF-I to the IGF1R results in autophosphorylation of the intracellular β-subunit and activation of intracellular signaling. Objective: The objective of this study was to evaluate the functional characte...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2006-08, Vol.91 (8), p.3062-3070
Main Authors: Walenkamp, M. J. E, van der Kamp, H. J, Pereira, A. M, Kant, S. G, van Duyvenvoorde, H. A, Kruithof, M. F, Breuning, M. H, Romijn, J. A, Karperien, M, Wit, J. M
Format: Article
Language:English
Subjects:
Adult
Base Sequence
Biological and medical sciences
Body Height
Bone Density
DNA Mutational Analysis
DNA, Complementary - chemistry
Endocrinopathies
Failure to Thrive - genetics
Female
Fetal Growth Retardation - genetics
Fibroblasts - metabolism
Fundamental and applied biological sciences. Psychology
Glutamic Acid
Growth Disorders - genetics
Heterozygote
Humans
Infant
Insulin-Like Growth Factor I - analysis
Insulin-Like Growth Factor I - metabolism
Insulin-Like Growth Factor I - pharmacology
Lysine
Medical sciences
Microcephaly - genetics
Mutation, Missense - genetics
Phosphorylation
Polymerase Chain Reaction
Receptor, IGF Type 1 - genetics
Receptor, IGF Type 1 - physiology
Sequence Analysis, DNA
Signal Transduction - drug effects
Vertebrates: endocrinology
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Summary:Context: The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding of IGF-I to the IGF1R results in autophosphorylation of the intracellular β-subunit and activation of intracellular signaling. Objective: The objective of this study was to evaluate the functional characteristics of a novel IGF1R mutation and describe the phenotypic features of two patients with this mutation. Design: The study was performed in a university hospital. Patients: We describe a 35-yr-old female with mild intrauterine growth failure, progressive postnatal growth retardation, severe failure to thrive, and microcephaly. Her daughter was born with severe intrauterine growth retardation and also showed postnatal failure to thrive and microcephaly. Results: We found a heterozygous G3148→A nucleotide substitution in the IGF1R gene, changing a negatively charged glutamic acid at position 1050 into a positively charged lysine residue (E1050K). E1050 is a conserved residue in the intracellular kinase domain. Dermal fibroblasts of the mother showed normal binding of iodinated IGF-I, but autophosphorylation and activation of downstream signaling cascades upon challenging with IGF-I was markedly reduced. Consequently, the maximal [3H]thymidine incorporation upon challenge with a dose range of IGF-I was reduced compared with a panel of control cells (3.65 ± 1.79-fold vs. 6.75 ± 4.7-fold stimulation; P < 0.01). These data suggest that the mutation results in the inactivation of one copy of the IGF1R gene. Conclusions: These two patients support the key role for IGF-I in intrauterine and postnatal growth. The different phenotypes of these and earlier described patients may be associated with variability in IGF-I signaling. The degree of intrauterine growth retardation may be partially determined by the presence or absence of maternal IGF-I resistance.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2005-1597