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. Author manuscript; available in PMC: 2012 Jan 1.
Published in final edited form as: Am J Med Genet A. 2011 Jan;155A(1):91–97. doi: 10.1002/ajmg.a.33781

IGF1R Variants Associated with Isolated Single Suture Craniosynostosis

Michael L Cunningham 1,2,3, Jeremy A Horst 3, Mark J Rieder 4, Anne V Hing 1,2, Ian B Stanaway 4, Sarah S Park 1,2, Ram Samudrala 3,5, Matthew L Speltz 6,1
PMCID: PMC3059230  NIHMSID: NIHMS243898  PMID: 21204214

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 nonsyndromic 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.

Keywords: craniosynostosis, IGF1R, non-syndromic, isolated, simple, sagittal, coronal, metopic, resequencing, non-synonymous SNP

INTRODUCTION

The birth prevalence of isolated craniosynostosis is 1/1,700–2,500 live births [French et al., 1990; Shuper et al., 1985], while the prevalence of the syndromic forms (hereditary forms with extracranial malformations) is approximately 1/25,000 [Cohen, 1979; Meyer, 1981]. Mutations in TWIST1, FGFR1, FGFR2, FGFR3, EFNB1, TGFBR1 and TGFBR2 have been described in cases of single suture craniosynostosis [Passos-Bueno et al., 2008]; however, extracranial manifestations are common and, with the exception of FGFR3P250R, isolated single suture craniosynostosis is exceptionally rare in the presence of these mutations. In this study we utilized resequencing to identify rare and private mutations in candidate genes selected on the basis of involvement with syndromic craniosynostosis or cranial suture biology. We report on 3/186 individuals with non-synonymous variants in IGF1R that were not observed in 1000 control genomes (2000 chromosomes) and two rare IGF1R variants that occurred in 0.1 – 0.3% of controls.

The occurrence of cytogenetic rearrangements in children with craniosynostosis is well described. Among individuals with craniosynostosis and associated malformations and/or developmental delay, approximately 10–16% will have detectable chromosome abnormalities [Cohen and MacLean, 2000; Passos-Bueno et al., 2008]. Even though rare cytogenetic rearrangements may not account for a large number of affected individuals, detection of such events can point to mutations that cause human malformation. Through a detailed review of the literature, we have catalogued 13 chromosomal aberrations for which two or more individuals with craniosynostosis have been reported. In addition to regions known to harbor known craniosynostosis genes 5q35 duplication (MSX2) and 7p21 deletion (TWIST1) [Howard et al., 1997; Ma et al., 1996; Sood et al., 1996], we found five additional chromosomal regions containing genes involved in calvarial development including TGFB2 (1q41), FGF2 (4q26), IGF2R (6q26), IGFBP1/IGFBP3 (7p14) and notably for this study, IGF1R (15q25-qter) [Adab et al., 2002; Ben Lagha et al., 2006; Cano-Gauci et al., 1999; Fulzele et al., 2007; Gabbitas and Canalis, 1998].

In total, there have been six case reports of trisomy (or tetrasomy) of chromosome 15q25-qter (inclusive of the IGF1R locus) in individuals with craniosynostosis (sagittal, metopic, and multisuture synostosis), indicating a potential role for dosage of IGF1R in premature suture fusion [Hu et al., 2002; Nagai et al., 2002; Pedersen 1976; Van Allen et al., 1992; Van den Enden et al., 1996; Zollino et al., 1999]. Additionally, postnatal overgrowth has been reported in individuals with extra copies of the IGF1R gene [Kant et al., 2007], whereas growth retardation is noted in those with monosomy 15q26 (IGF1R) [Veenma et al., 2009], suggesting a dosage effect on a growth stimulatory gene.

IGF1R, located at 15q26.3, is a tyrosine kinase growth factor receptor with significant homology to the insulin receptor (INSR) and serves as the receptor for both IGF-I and IGF-II. IGF-I and IGF1R are both expressed in the developing cranial sutures, where they regulate bone growth and increase expression in response to tensile force [Bradley et al., 1999; Hirukawa et al., 2005; Roth et al., 1997]. In a mouse explant suture model, exogenous IGF-I has been shown to induce increased expression of osteocalcin, osteopontin, alkaline phosphatase, and type 1 collagen [Chen et al., 2003]. Furthermore, increased systemic thyroxine exposure, a known cause of craniosynostosis in humans, leads to increased IGF-I expression in the sagittal suture [Akita et al., 1996]. An interaction between IGF1R and fibronectin has been shown to inhibit apoptosis in pancreatic carcinoma cell lines through IGF1R transactivation [Edderkaoui et al., 2007]. The occurrence of overgrowth and craniosynostosis in humans with IGF1R trisomy/tetrasomy, its proliferative and anti-apoptotic activities, and its role in bone growth suggests that gain-of-function mutations in IFG1R could lead to craniosynostosis.

In this manuscript we describe five individuals with isolated single suture craniosynostosis associated with either private or exceptionally rare variants of IGF1R. We suggest that individuals with mutations in IGF1R have an increased risk of developing craniosynostosis.

MATERIALS AND METHODS

Participants and DNA Sample Preparation

We obtained independent prospective institutional review board (IRB) approval from each participating center: including Seattle Children’s Hospital, Northwestern University in Chicago, Children’s Heath Care of Atlanta, and St. Louis Children’s Hospital. This study is HIPAA compliant.

Participants were enrolled in a previously described, prospective, four-center investigation of neurodevelopment among children with single suture craniosynostosis [Speltz et al., 2007]. Infants were eligible if, at the time of enrollment, they had isolated sagittal, unilateral coronal, metopic, or unilateral lambdoid synostosis confirmed by CT scan. Lambdoid synostosis cases were excluded from the present study due to insufficient numbers. Exclusion criteria included presence of major medical or neurological conditions; presence of three or more minor extra-cranial malformations [Leppig et al., 1987]; or presence of other major malformations.

Enrolled cases in the overall study were 84% of those eligible, with distance or time constraints being the major reason for nonparticipation. CT scans were performed at each participating center and used for diagnosis confirmation. Neurodevelopmental data were available for 136 cases enrolled in the present study. We administered two standardized, norm-referenced tests at age 3, the Bayley Scales of Infant Development—2nd Edition (BSID-II) [Black and Matula, 1999] and the Preschool Language Scale, Third Edition (PLS-3) [Zimmerman, 1991]. DNA was isolated with routine methods. Prior to enrollment in this study all cases were screened for hot-spot mutations in FGFR1, FGFR2, FGFR3, TWIST1, and MSX2 [Seto et al., 2007], and all females for mutations in EFNB1 (data not shown) and excluded from this study if a causative mutation was identified. Each of these genes was resequenced in enrolled cases to identify novel variants outside of mutation hotspot regions.

Resequencing

DNA from 186 craniosynostosis cases (46 coronal, 46 metopic, 94 sagittal) and 95 screening control genomes (Coriell, Camden, NJ) drawn from major US populations (African/African-American, European, Asian {Chinese/Japanese} and Hispanic), used previously as part of the NIEHS-SNPs Environmental Genome Project, were used for candidate gene resequencing. Twenty-seven candidate genes chosen on the basis of involvement with syndromic craniosynostosis and/or suture development (EFNB1, FGFR1, FGFR2, FGFR3, MSX2, NELL1, TWIST1, EFNA4, FGF2, RUNX2, SNAI1, TWIST2, TGFβR1, TGFβR2, ALX4, BMP2, BMP3, BMP4, BMP7, IFG1R, IGF-I, IGF2R, IGFBP1, IGFBP5, TGFβ1, TGFβ2, and TGFβ3) were sequenced in all coding regions, splice junction sites, and 5′ and 3′ untranslated regions.

Control Genotyping

Genetic variants identified in the candidate genes of cases, but not the 95 Coriell controls, were subjected to site-specific genotyping in a sample of 1012 control samples sourced from 480 Sigma Human Random Control DNA samples (HRC-1 thru HRC-5, Sigma, St. Louis, MO), 421 de-identified clinical samples from Seattle Children’s Hospital, 92 Coriell samples (unique from the screening controls), and 19 samples from subjects with Mendelian disorders with a previously identified molecular cause. The identification of five rare variants in the coding region of IGF1R led to further analysis of conservation at the nucleotide and amino acid level as well as protein modeling.

Amino Acid Conservation and GERP Scores

Each variant of interest identified in IGF1R was analyzed for evolutionary conservation using the NCBI Multiple Alignment Viewer within Blink [http://www.ncbi.nlm.nih.gov]. Greater evolutionary conservation was used to prioritize variants for further investigation. In addition to measures of evolutionary conservation at the amino acid level, GERP scores were used as an alternative prioritization tool [Goode et al., 2010]. The GERP score estimates the difference between observed rates of evolution at a given site at the nucleotide level and that expected assuming neutral evolution. A score greater that 4 has been shown to enrich for mutations that cause Mendelian disease [Cooper et al., 2010].

Protein Conformation – Modeling the IGF1R-IGF-I Hetero Quaternary Structure

We built a comprehensive insulin receptor oligomer using the repeating crystal unit cell contacts from the most recent and representative extracellular structure (PDB identifier 2 dtg) [Berman et al., 2000]. We identified the dimers spanning the unit cell border as physiologic by evaluating monomer to monomer crystalization artifacts and mapping known mutations associated with insulin resistance. The selected chains are the same as those resulting from previous informatic analysis [Renteria et al., 2008]. Using this structure as a template, we substituted in the available portion of the IGF1R structure (residues E31-E489; PDB identifier 1igr) [Garrett et al., 1998]. We converted the remaining globular extracellular portion of the insulin receptor to represent IGF1R by mutating side chains with SCWRL4 [Krivov et al., 2009]. We rebuilt missing loops with both loop building options in the RAMP suite: phi/psi search and segment matching, [http://software.compbio.washington.edu/ramp/ramp.html] and selected loops using Bayesian analysis of inter residue contacts [Samudrala and Moult, 1998]. We docked the IGF-I ligand into the resulting IGF1R homodimer model in the conformation proposed by Epa and Ward [Epa and Ward, 2006]. Finally, we rotated domain 3 (L2) around the ligand from the conformation in the 1igr structure to that of insulin in the 2dtg structure, as suggested in the 1igr structure paper [Garrett et al., 1998]. The resulting modeled homodimer presents a cavity with matching topology to IGF-I, and so we present this as the most representative model to date for the IGF1R - IGF-I hetero quaternary structure. Upon this model we mapped all mutations published for IGF1R (selected data shown) and those novel mutations reported here.

RESULTS

Resequencing 27 candidate genes in 186 cases yielded 1383 polymorphisms. Forty-nine of these polymorphisms were confined to cases (e.g. not seen in screening 95 Coriell genomes). Genotyping of these 49 SNPs in 1012 control genomes resulted in the identification of 15 private variants in fourteen cases (one each in BMP3, BMP4, EFNB1, FGF2, NELL1, TGFB3, 2 each in IGF2R, TGFBR2, and TGFB2). Five variants were identified in IGF1R (Table I), with three being exclusive to a case subject and two found to be exceptionally rare (control minor allele frequency 0.0005 and 0.0032). None of these 5 cases had private or rare variants identified in other candidate genes.

Table 1. Novel and rare IGF1R variants associated with isolated craniosynostosis.

R406H (case 1), R595H (case 2), N857S (case 3) variants were identified in cases but not in 916, 852, and 930 genomes, respectively. The mother of case 1 was found to carry the R406H variant. She was not examined but was not reported to have evidence of synostosis. The variants in cases 2 and 3 were each identified in dbSNP (rs56248469 and rs45611935, respectively). In both cases dbSNP recorded a single occurrence in a cancer registry and in neither phenotype nor sample size was reported. Subsequent to enrollment case 5 was found to have stridor, a pituitary cyst, and developmental delays. In all cases the amino acid residues and nucleic acid sequence (GERP score) [Goode et al.] suggested a high level of conservation (GERP score above our threshold of 4 in all five cases). Rare variants P190S (case 4) and M446V (case 5) were seen in the control sample with minor allele frequencies of 0.0005 and 0.0032 respectively. Of note, there are 240 arginine to histidine mutations in the 7,022 disease associated nsSNPs listed in OMIM, such that mutations such as seen in cases 1 and 2 are enriched 13 fold for disease phenotypes with respect to random.

Case Suture Domain Variant MAF cases (n) MAF controls (n) SNP Conservation GERP
Private Variants
1 Sagittal Recep_L_domain IGF1R-ARG-0406-HIS 0.003 (1/186) 0.000 (0/916) 0 fish 5.4
2 Coronal - IGF1R-ARG-0595-HIS 0.003 (1/186) 0.000 (0/852) rs56248469 mouse, marsupial 4.6
3 Sagittal FN3 domain IGF1R-ASN-0857-SER 0.003 (1/186) 0.000 (0/930) rs45611935 fish 5.5
Rare Variants
4 Coronal Furin-like cysteine rich region IGF1R-PRO-0190-SER 0.003 (1/186) 0.0005 (1/936) 0 mouse 4
5 Coronal Recep_L_domain IGF1R-MET-0446-VAL 0.003 (1/186) 0.0032 (6/931) 0 mouse 5.4
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MAF- minor allele frequency

SNP- data from SNP database

Mapping IGF1R Mutations onto the IGF1R/IGF-I Hetero Quaternary Structure

We used the known crystalline structures of IGF1R, INSR, and IGF-I to interpret the location and potential functional significance of the amino acid variants identified in our cohort. Using this method we have determined that all three private variants (R406H, R595H, and N857S) occur in amino acid residues that are located on the external surface of the IGF1R quaternary structure (Figure 1). In the presented dimeric orientation and all those previously proposed, the mutated residues are exposed with respect to the homodimer partner, the IGF-I binding site, and the cell membrane.

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

Figure 1

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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.

The R406H (domain 3, L2, receptor L-domain) and R595H (domain 4, FN III-0, fibronectin 3 domain) mutations are co-located on the protein surface despite the long intervening sequence of 189 amino acids (Figure 1). The intervening surface forms a concavity (Figure 1), which collects relatively large patches of hydrophobicity (Fig 2).

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

Figure 2

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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.

The N857S variant presents in domain 6 on the side opposite the homodimer interface, at the corner of the lateral surface of the construct. There are no previous reports of mutations in IGF1R or the insulin receptor in the immediate area (Figs 1, 3). The rare variants identified in our study (P190S and M446V) demonstrate a high level of conservation at the amino acid and nucleotide (GERP score) level. P190S presents at a similar distance from the cell membrane, similarly exposed at the opposite side of the construct stalk to the private variant N857S (Fig 1). M446V is in close proximity to the private variants R406H and R595H. Clustering of these private and rare variants identified in cases of craniosynostosis suggests a functional relationship.

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

Figure 3

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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.

Neurodevelopmental Features of Cases with IGF1R Variants

We compared the average BSID-II and PLS-3 standard scores for the five cases with identified rare IGF1R variants with the average standard scores of all other enrolled cases for whom we had test data (n = 136). As the IGF1R variant case sample was too small for meaningful interpretation of inferential statistics, we calculated only means, standard deviations and effect sizes [Cohen, 1992], which are shown in Table II. At age 3, the mean BSID-II and PLS-3 scores of cases with rare IGF1R variants were approximately 2/3 of a standard deviation lower than the mean scores generated by other cases of synostosis for whom we had psychometric test data. However, there was substantial variation in test scores among these 5 cases with IGF-1R variants and the possibility of association between this mutation and neurodevelopmental status requires confirmation in larger samples.

Table 2. Neurodevelopmental test scores for subjects with IGF1R variants.

(MDI) Mental Development Index. (PDI) Psychomotor Development Index. (Mean) Standard, norm-referenced scores with a population mean of 100, SD = 15. (d ) Difference between the two means divided by the pooled standard deviation in this sample.

Neurodevelopmental Test (at age 3) Cases with IGF1R Variants Cases without IGF1R Variants Effect
(n = 5) (n = 131) Size (d)
Mean SD Mean SD
BSID-II MDI 79.4 23.3 93.5 12.9 0.75
BSID-II PDI 81.8 17.3 91.6 13.6 0.63
PLS-3 84.2 17.8 96.9 14.3 0.78
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MDI = Mental Development Index

PDI = Psychomotor Development Index

Mean = Standard, norm-referenced scores with a population mean of 100, SD = 15.

d = difference between the two means divided by the pooled standard deviation in this sample

DISCUSSION

We report on three cases of isolated sagittal or coronal craniosynostosis with private mutations in insulin-like growth factor I receptor (IGF1R) that occur in highly conserved residues on the surface of the functional IGF-I - IGF1R quaternary structure, opposite to the IGF1R homodimer interface, and far from the binding cavity of IGF-I. Previous to this study, no mutations have been described that map to the IGF1R or insulin receptor surface at these variant sites. Previously reported mutations in the extracellular portion of IGF1R are associated with growth retardation, and are primarily confined to the IGF-I interface (Figure 1, shown in purple). Although postnatal growth information for our cases is not available, trisomy and tetrasomy including 15q26.3 (the chromosomal location of IGF1R) is associated with overgrowth and craniosynostosis [Hu et al., 2002; Kant et al., 2007; Nagai et al., 2002; Pedersen 1976; Van Allen et al., 1992; Van den Enden et al., 1996; Zollino et al., 1999], suggesting an IGF1R gain of function phenotype.

The R406H and R595H residues are separated far in sequence space but physically close even for neighboring domains (23 Å between α-carbons; the diameter of the homodimer construct is 130–150 Å). These residues likely function in the same protein interaction, as they span a hydrophobic surface patch postulated to contribute to protein interaction specificity (Figure 2) [Garrett et al., 1998]. This hydrophobic surface may interact with a large multidomain protein such as fibronectin, or a subsidiary partner thereof. Enhanced interaction with fibronectin could increase its proposed prosurvival effect [Edderkaoui et al., 2007], thereby increasing the IGF1R signal as a gain of function mutation. Furthermore, the rare variant M446V is in close physical proximity to these private variants. We hypothesize that this protein-binding event is integral to maintaining suture patency during calvarial development.

Previously described missense mutations in the extracellular domains of IGF1R are all associated with growth retardation [Abuzzahab et al., 2003] and are presumed to lead to loss of IGF1R function. The V599E mutation is thought to result in abnormal protein trafficking [Wallborn et al., 2010], the R511Q mutation decreases intracellular signaling response to IGF-1 [Inagaki et al., 2007], the G1125A (a kinase domain mutation) results in a dominant-negative effect [Kruis et al., 2010], and a homozygous nonsense mutation C821 Term [Jospe et al., 1996] and a 95 kb deletion of exons 11–21 of IGF1R [Veenma et al., 2009] have each been associated with short stature or multiple anomalies associated with growth deficiency. Each of the mutations associated with growth deficiency occur in either the ligand binding site or lead to receptor loss of function. The one extracellular IGF1R missense mutation associated with growth retardation not shown (R709Q; template not available for the 675–774 region) is spanned closely by positions that significantly decrease or abrogate IGF-I affinity when mutated to alanine [Mynarcik et al., 1997; Whittaker et al., 2001]. In contrast, the three novel mutations and two rare variants we describe herein present in a consistent spatial distribution different from those previously seen for the disease phenotypes of IGF1R (Figure 1) or insulin receptor missense mutations (Figure 3).

While also residing on the surface of the extracellular domain of IGF1R, the N857S mutation is not in the same domain as the other two mutations. This variant presents in a cleft not present in the insulin receptor, between a positively charged region of domain 5 and a negatively charged region of domain 6. This interdomain cleft is opposite the terminal extent of the homodimer interface, at which resides the P190S variant site. The proximity of the N857S and P190S variants to the homodimer interface endpoint may describe increased autodimerization, a second postulated mechanism for overgrowth by upregulating IGF1R signaling.

In summary, we have identified private mutations of IGF1R in three cases of isolated sagittal or coronal craniosynostosis (R406H, R595H, and N857S). Each of these mutations occurred in residues on the surface of the extracellular domains distant from the IGF binding domain. The rarity of these mutations (<1/2000 chromosomes), their location in probable protein-binding sites, their co-location with rare variants associated with craniosynostosis (P190S and M446V), and the role of IGF1R in the development of cranial sutures and regulation of osteoblast proliferation suggest that these, and potentially other mutations in IGF1R, play a role in the pathogenesis of craniosynostosis. In addition, we have tentatively identified among cases with single-suture craniosynostosis an association between IGF1R mutations and elevated risk of neurodevelopmental delay. Future studies of patients with IGF1R-associated craniosynostosis will help to elucidate the clinical significance of these mutations. Our ongoing investigation will include in-vitro functional analysis and replication of these data in another large craniosynostosis cohort.

Acknowledgments

This work was supported by NIH grants NIH/NIDCR R01 DE018227 (MLC), NIH/NIDCR R01 DE013813 (MLS), and the Jean Renny Endowment for Craniofacial Research (MLC). We wish to thank Linda Peters for her assistance in the collection of samples used to for DNA isolation and Jerrie Bishop for her assistance in manuscript preparation.

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