IGF1R variants associated with isolated single suture craniosynostosis

Abstract

The genetic contribution to the pathogenesis of isolated single suture craniosynostosis is poorly understood. The role of mutations in genes known to be associated with syndromic synostosis appears to be limited. We present our findings of a candidate gene resequencing approach to identify rare variants associated with the most common forms of isolated craniosynostosis. Resequencing of the coding regions, splice junction sites, and 5' and 3' untranslated regions of 27 candidate genes in 186 cases of isolated non-syndromic single suture synostosis revealed three novel and two rare sequence variants (R406H, R595H, N857S, P190S, M446V) in insulin-like growth factor I receptor (IGF1R) that are enriched relative to control samples. Mapping the resultant amino acid changes to the modeled homodimer protein structure suggests a structural basis for segregation between these and other disease-associated mutations found in IGF1R. These data suggest that IGF1R mutations may contribute to the risk and in some cases cause single suture craniosynostosis.

Copyright © 2010 Wiley-Liss, Inc.

Figures

Figure 1. Structural basis for segregation between disease-associated mutations found in IGF1R

Two IGF1R monomers are each shown with rainbow coloring from amino terminus in blue to carboxy terminus in red (left panel). Only the extracellular domains are represented here. Mapping the novel (red side chains) and rare (yellow side chains) IGF1R missense mutations reveals segregation with respect to mutations associated with growth deficiency (purple side chains), which occur principally at the ligand binding site for IGF-I (grey). Middle panels are oriented with a view from the extracellular space towards the cell membrane; the R406H and R595H mutations both occur within a large elongated concavity (see red side chains in lower middle panel) exhibiting contours and hydrophobicity suggestive of a protein interaction site (see Fig 2). Surface models (right and lower middle) demonstrate that each novel mutation (R406H, R595H, and N857S) are on the protein surface. M446V is in close proximity with R406H and R595H. In the left panel the N857S and P190S mutations are seen to co-localize at the terminal extent of overlap for the dimer interface.

Figure 2. R595H and R406H map to rim of IGF1R hydrophobic concavity

The R595H and R406H variants (shown with red side chains outlined in green) present in a hydrophobic concavity suggestive of a nonobligate protein interaction. The IGFI-IGF1R heterooligomer surface is shown colored by hydropathicity: hydrophobic surface patches shown as orange, neutral as white, hydrophilicity as blue. A series of hydrophobic patches form the rim of a concavity approximately 15 Ångstroms in depth and 30 Ångstroms at maximum width. The remaining protein surface is fogged to highlight the concavity, and show the relatively sparse hydrophobicity on the remaining IGF1R surface. Both R595H and R406H private variants map to the rim of this concavity, possibly providing interactions essential to a protein interaction relevant to IGF1R signaling. Orientation: the cell membrane would be at the bottom of image.

Figure 3. Insulin receptor missense mutations associated with insulin resistance or leprechaunism

Depiction of the insulin receptor dimer and insulin ligand is analogous to those of IGF1R and IGF-I in Figure 1, respectively. The insulin receptor is shown with rainbow coloring from amino terminus in blue to carboxy terminus in red. The insulin ligands are shown in grey. Side chains of previously described missense mutation sites are shown in purple. The mutation sites cluster, in a pattern describing deleterious effects on receptor folding or ligand binding. The IGF1R mutations described in this manuscript are at unique sites with respect to those previously described for the insulin receptor.