Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. Case Presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

  • IGF1R mutations impact growth and glucose metabolism.

  • IGF1R signaling modulates immune function, as demonstrated by in vitro human and in vivo mouse studies.

  • The novel heterozygous IGF1R mutation, c.641-2A>G, results in abnormal mRNA splicing and premature IGF1R termination.

  • IGF1R mutation carriers demonstrated varied phenotypic expression, with growth failure in twin probands and hypoglycemia, reduced Th17, and increased Th1 cell percentages in all affected family members.

Growth and glucose homeostasis are intricately regulated by hormonal insulin and insulin-like growth factor (IGF) signaling via tyrosine kinase receptors, including the IGF1 receptor (IGF1R) [1]. The IGF1R gene is found on chromosome 15q26.3 and consists of 21 exons, encoding for an (αβ)2 homodimer with homology to the insulin receptor (IR) [2]. Mutations in IGF1R have been reported to affect ligand binding and/or decrease surface IGF1R expression [2]. Prior reports of IGF1R mutations are commonly heterozygous [3-15], with only 2 compound heterozygous [16, 17] and 2 hypomorphic homozygous mutations [14, 18] reported to date. Homozygous loss-of-function mutations are likely lethal, as observed in mouse studies [19].

IGF1R mutations are known to cause intrauterine growth retardation, microcephaly, and failure to thrive postnatally [2, 20, 21]. The current therapy for rectifying growth defects associated with heterozygous IGF1R mutations is trial administration of recombinant human growth hormone (rhGH) intended to induce supraphysiologic levels of IGF1, in complex with stabilizing IGF-binding protein-3 (IGFBP-3), providing compensatory IGF1R signaling through the wild-type IGF1R allele [22]. In addition to growth defects, direct effects on glucose metabolism, including glucose intolerance, have been observed [13-15, 17, 23]. Hypoglycemia has been less frequently reported [24].

IGF1R is found to be ubiquitously expressed in most cells of the body including muscle, adipose, and bone, as well as innate and adaptive immune cells [25]. While IGF1R expression is known to be decreased on peripheral blood mononuclear cells (PBMCs) of subjects with IGF1R mutations [26, 27] and IGF1R signaling has been associated with modulation of immune function [25], there is limited understanding of the impacts of IGF1R on human innate and adaptive immunity in vivo. Although IGF1R mutations have not been associated with overt immune defects, we hypothesized that these mutations may be associated with subclinical immune phenotypic alterations. Information gained could potentially elucidate immune mechanisms in disorders with known IGF1 or IGF1R modulation. Here, we report a novel heterozygous IGF1R mutation, c.641-2A>G, leading to a splicing defect that impairs IGF1R protein expression, altering the growth, glucose metabolism, and immune profile of affected subjects.

Subject Enrollment

All procedures were approved by local Institutional Review Boards and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from participants (or their legal guardian in the case of minors) prior to enrollment. Subjects affected by the IGF1R mutation were age- and sex-matched to 1 or 2 control subjects attending clinics at the University of Florida (UF; Gainesville, FL) and Emory University (Atlanta, GA). Peripheral blood samples were collected from nonfasted subjects by venipuncture in sodium heparin vacutainer tubes for IGF1R expression experiments and ethylenediaminetetraacetic acid-coated vacutainer tubes (BD Biosciences) for immune phenotyping experiments. Blood was rested overnight prior to processing to minimize variance due to transport times. Subject demographic information is presented in online suppl. Tables 1, 2 (for all online suppl. material, see www.karger.com/doi/10.1159/000510764).

Glucose Metabolism, IGF, and IGFBP Quantification

Serum glucose was determined via the hexokinase method and hemoglobin A1c by cation-exchange chromatography, performed by UF Health Pathology Laboratories. Serum IGF1 levels were measured by the enzyme-labeled chemiluminescent immunometric assay, performed by either Quest Diagnostics or UF Health Pathology Laboratories. IGFBP-3 and IGFBP-1 levels were measured by quantitative chemiluminescent immunoassay and quantitative radioimmunoassay, respectively, both performed by ARUP Laboratories.

Genetic Analysis

Genomic DNA extracted from whole blood was used for whole exome sequencing and Sanger dideoxy sequencing. Whole exome sequencing for twin B was performed by Baylor Genetics, as previously described [28]. VCRome 2.1 in-solution exome probes [29] and additional probes for genes involved in over 3,600 Mendelian diseases were used for exome enrichment. For targeted IGF1R sequencing, coding exon 3, including intron-exon junctions, was PCR amplified and sequenced as previously described [5]. The intronic primers for amplifying exon 3 were as follows: forward, IGF1Rx3f (intron 2), 5′-GCAGTGAATGACCCAGAAGGATGC-3′; reverse, IGF1Rx3r (intron 3): 5′-CCGACAGAGTCTA-CCTTTGTGTGCTA-3′. Total RNA was extracted from PBMCs that were ficoll purified from whole blood and subjected to RT-PCR amplification to assess aberrant splicing of exon 3. The primers for amplifying cDNA sequences between exon 2 and exon 4 were forward, (exon 2) 5′-GAGAGCCTCGGAGACCTCTTCC-3′; reverse (exon 4), 5′-CTTCGGGCAAGGACCTTCACAA-3′. Microarray cytogenetic testing was performed via oligonucleotide-single nucleotide polymorphism assays by Agilent Sureprint G3 human CGH + SNP for twin A and Affymetrix CytoScan HD for twin B.

Flow Cytometric IGF1R Quantification

200 μL of whole blood was stained with anti-human CD221-PE (1H7; Biolegend) for 30 min at 23°C in the dark. Red blood cells were lysed for 5 min at 23°C with 1-step Fix/Lyse Solution (eBioscience), followed by 3 washes with staining buffer (PBS + 2% FBS + 0.05% NaN3). Events were acquired on LSRFortessa (BD Biosciences) and analyzed with FlowJo software (v10.6.1; Tree Star).

Whole Blood Immune Phenotyping

200 μL of whole blood was stained with 6 different panels of fluorescently labeled anti-human antibodies, adapted from a standardized immunophenotyping panel published by Maecker et al. [30], for 30 min at room temperature in the dark. Antibody information is presented in online suppl. Table 3. Red blood cells were lysed for 5 min at 23°C with 1-step Fix/Lyse Solution (eBioscience), followed by 3 washes with staining buffer. Events were acquired on LSRFortessa (BD Biosciences) and analyzed with FlowJo software (v10.6.1; Tree Star).

Statistical Analyses

Data were analyzed using GraphPad Prism software version 7.0. Data are presented as mean ± standard deviation unless otherwise specified. IGF1R expression was compared between IGF1R c.641-2A>G heterozygous (IGF1RHet) subjects and unrelated control subjects via the Mann-Whitney U test. Frequencies of broad immunophenotypes were compared using multiple t tests without correction for multiple comparisons, to accommodate the small number of IGF1RHet subjects available for analysis. Frequencies of selected immunophenotypes were compared using the Mann-Whitney U test in secondary analyses. p values <0.05 were considered significant.

Clinical Presentation of Family Members Carrying the IGF1R c.641-2A>G Mutation

Twin monozygotic female probands were born at 34-week gestation via caesarean section due to preterm premature rupture of membranes. Twin A had a birth weight of 1.53 kg (−1.51 standard deviation score [SDS] Fenton preterm growth chart), birth length of 43.2 cm (−0.31 SDS Fenton), and head circumference of 29 cm (−1.10 SDS Fenton). Twin B had a birth weight of 1.53 kg (−1.51 SDS Fenton preterm growth chart), birth length of 42 cm (−0.75 SDS Fenton), and head circumference of 29.5 cm (−0.77 SDS Fenton). The twins had hypotonia in infancy with failure to attain catch-up growth (in weight and length) in the first 2 years of life. Head circumferences were >2 SDS below the mean from 6 months to 2 years. Twin B also had congenital scoliosis with multiple fused hemivertebrae, tethered cord, and Chiari malformation. The twins had microarray-based comparative genomic hybridization testing which showed a 7q31.1 deletion (242–317 kb) of unknown clinical significance. The only coding gene in the deleted region is IMMP2L, which has not been linked with any phenotypes in the Online Mendelian Inheritance in Man database. While Immp2l knockout mice have been reported to show decreased body weight prior to adulthood, there is evidence of haplosufficiency [31], suggesting that the 7q31.1 deletion observed in the twins is unlikely to be the cause of their failure to thrive.

Both were evaluated by a pediatric endocrinologist at 3 years 4 months of age for short stature. At that time, twin A weighed 11.6 kg (SDS −2.08) with a height of 87.7 cm (SDS −2.21). Twin B weighed 11.4 kg (SDS −2.4) with a height of 86 cm (SDS −2.65). Twin A also experienced hospital admission at age 3 for decreased responsiveness and hypoglycemia (46 mg/dL) in the setting of acute otitis media and 16 h of fasting. During the ensuing 2 years of follow-up, they experienced intermittent episodes of mild hypoglycemia (55–70 mg/dL) on a home glucometer, mostly during prolonged fasting.

The combination of failure to thrive (low weight and short stature), hypotonia, and microcephaly was concerning for an underlying genetic etiology, and whole exome sequencing was obtained for twin B revealing a likely pathogenic heterozygous mutation of IGF1R (c.641-2A>G). Additional heterozygous variants of unknown significance were detected in twin B (online suppl. Tables 4, 5) although these were unlikely to be associated with the clinical observations. Of the heterozygous X-linked and autosomal dominant mutations identified, the novel c.3008C>T variant in KMT2A is the only mutation that could account for some, but not all, of their phenotypes (online suppl. Table 4). Other mutations in this gene are associated with Wiedemann-Steiner syndrome, which presents with short stature and hypotonia [32]. However, the amino acid change from the novel mutation in twin B is predicted to have a benign impact on KMT2A structure and function (online suppl. Table 4). A number of autosomal recessive variants of unknown clinical significance were also observed in twin B (online suppl. Table 5). Interestingly, 2 of the mutations were associated with microcephaly (online suppl. Table 5); however, as heterozygous recessive variants, these mutations would again be unlikely to be the underlying etiology for this observation in the twins. Overall, the whole exome sequencing results support the heterozygous IGF1R mutation (c.641-2A>G) as the causative mutation responsible for the phenotypes observed.

Growth factor testing revealed IGF1 levels were within normal reference ranges in both twins (twin A: 154 ng/mL and twin B: 115 ng/mL, reference range 55–248) (Fig. 1a). Likewise, IGFBP-3 levels were within normal reference ranges for both twins (twin A: 4,460 ng/mL and twin B: 3,630 ng/mL, reference range 2,169–4,790) (Fig. 1b). Random growth hormone levels were elevated or within normal reference ranges at 9.11 and 2.59 ng/mL (reference range 0.1–6.2), for twins A and B, respectively. Their weight tracked along the first–fifth percentile but with appropriate BMI and only mildly decreased prealbumin levels (14–16 mg/dL, reference range 20–40). They exhibited a mild bone age delay of 1 year 4 months at initial presentation and appropriate thyroid function. They were started on subcutaneous rhGH at 4 years 3 months of age (dosing 0.3 mg/kg/week) at a height of 93.2 cm (SDS −2.15) and 90.8 cm (SDS −2.74) for twins A and B, respectively. Height velocity improved with rhGH therapy (Fig. 1c) by inducing supraphysiologic IGF1 and IGFBP-3 levels (Fig. 1a, b), while hemoglobin A1c values did not rise significantly in either twin (5.2–5.4%, reference range <5.7). After 1 year of rhGH, twin A’s height SDS improved to −1.60 and twin B’s improved to −2.12. Mild hypoglycemia persisted after initiation of rhGH therapy, and intermittent supplementation with uncooked cornstarch (complex carbohydrate, i.e., slowly digested) and protein powder was utilized to stabilize blood glucose levels.

Fig. 1.

Clinical laboratory and growth data for probands (twin A and twin B). Serum IGF1 (a) and IGFBP-3 (b) levels with the vertical line indicating initiation of rhGH therapy and horizontal lines indicating the reference range at age 5 years (shaded area). c CDC age- and gender-based height growth chart for probands. Arrow at initiation of rhGH therapy. IGF1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor-binding protein-3; rhGH, recombinant human growth hormone.

Fig. 1.

Clinical laboratory and growth data for probands (twin A and twin B). Serum IGF1 (a) and IGFBP-3 (b) levels with the vertical line indicating initiation of rhGH therapy and horizontal lines indicating the reference range at age 5 years (shaded area). c CDC age- and gender-based height growth chart for probands. Arrow at initiation of rhGH therapy. IGF1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor-binding protein-3; rhGH, recombinant human growth hormone.

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The probands’ older sister was born at 41-week gestation. Her birth weight was 2.7 kg (SDS −1.31), birth length was 48.3 cm (SDS −0.48), and head circumference is unknown. She experienced hypoglycemia (48 mg/dL) at age 7. However, she did not have short stature with a height of 114 cm (SDS −1.55). Her weight, 17.5 kg (SDS −2.04), and BMI, 13.5 kg/m2 (SDS −1.58), were slightly low and attributable to stimulant medication use for attention deficit hyperactivity disorder, but with an appropriate prealbumin level of 21 mg/dL. She was found to have the same IGF1R heterozygous mutation with initial IGF1 level in the midnormal range (192 ng/mL; reference range 57–277) and elevated IGFBP-3 (5,920 ng/mL; reference range 2,188–4,996). Her IGFBP-1 level was 8 ng/mL (reference range 15–95) during mild hypoglycemia at age 7 with a serum glucose of 64 mg/dL (random venous draw). She was started on nightly cornstarch and protein supplementation and achieved normoglycemia.

Maternal and paternal adult heights were 157.5 cm (5′2″) and 180.3 cm (5′11″), respectively. The probands’ mother was born at 36-week gestation and weighed 2.44 kg (−0.37 SDS Fenton). She reported subjective symptoms of hypoglycemia, as did maternal grandmother and paternal grandfather (Fig. 2). The IGF1R sequencing revealed the same heterozygous mutation in the probands’ mother.

Fig. 2.

Pedigree of family with the IGF1R c.641-2A>G (het) variant. The twin female probands (arrows) are III-3 (twin A, P1) and III-4 (twin B, P2). Family members who had the IGF1R gene sequenced are noted with an asterisk (*) and those carrying the heterozygous mutation are noted with a plus sign (+). Family members with reported hypoglycemia are shaded gray and those with short stature are shaded black. Height standard deviation score (SDS) for age and sex based on CDC growth charts is found in parentheses (adult height SDS provided or most recent heights for children; twin proband height SDSs are before rhGH treatment). IGF1R, insulin-like growth factor 1 receptor.

Fig. 2.

Pedigree of family with the IGF1R c.641-2A>G (het) variant. The twin female probands (arrows) are III-3 (twin A, P1) and III-4 (twin B, P2). Family members who had the IGF1R gene sequenced are noted with an asterisk (*) and those carrying the heterozygous mutation are noted with a plus sign (+). Family members with reported hypoglycemia are shaded gray and those with short stature are shaded black. Height standard deviation score (SDS) for age and sex based on CDC growth charts is found in parentheses (adult height SDS provided or most recent heights for children; twin proband height SDSs are before rhGH treatment). IGF1R, insulin-like growth factor 1 receptor.

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Novel IGF1R c.641-2A>G Heterozygous Variant Drives Early IGF1R Protein Termination

We obtained genomic DNA from the affected family and conducted targeted sequencing after 1 proband (twin B) was found to have a mutation in IGF1R on whole exome sequencing. A likely pathogenic heterozygous variant, c.641-2A>G, was present in twin affected female probands, their mother, and one of their sisters (Fig. 2; online suppl. Fig. 1). The father and maternal half-sister do not carry the variant. This mutation was not present in the Genome Aggregation Database [33] or the Exome Sequencing Project [34] database at the time of this writing, and as such, is deemed novel. The mutation modified the 3′ acceptor splice site consensus sequence of intron 2, which was predicted to lead to skipping of exon 3, inducing a frameshift (Fig. 3). The predicted abnormal splicing event was confirmed by Sanger analysis of IGF1R cDNA from the probands (Fig. 4). This frameshift was predicted to lead to premature protein termination (p.Met214Thrfs*67) prior to the transmembrane domain, likely to impact IGF1R surface expression (Fig. 5). Additionally, the 2 ligand-binding sites for IGF1 in each αβ dimer, the first being composed of parts of the L1 and α-CT domains from different subunits and the second site composed of parts of Fn1 and Fn2 domains from the same subunit [35], were both predicted to be disrupted (Fig. 5).

Fig. 3.

IGF1R c.641-2A>G (het) variant induces early IGF1R protein termination. IGF1R c.641-2A>G (het) mutation (underlined) in the 3′ consensus sequence for spliceosomal recognition of intron 2 is predicted to induce skipping of exon 3, leading to premature protein termination. Gene diagram modified from ImmunoBase. NCBI reference sequence for gene: NG_009492.1; protein: NP_000866.1. IGF1R, insulin-like growth factor 1 receptor; WT, wild type.

Fig. 3.

IGF1R c.641-2A>G (het) variant induces early IGF1R protein termination. IGF1R c.641-2A>G (het) mutation (underlined) in the 3′ consensus sequence for spliceosomal recognition of intron 2 is predicted to induce skipping of exon 3, leading to premature protein termination. Gene diagram modified from ImmunoBase. NCBI reference sequence for gene: NG_009492.1; protein: NP_000866.1. IGF1R, insulin-like growth factor 1 receptor; WT, wild type.

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Fig. 4.

IGF1R c.641-2A>G (het) mutation induces skipping of exon 3. Targeted Sanger sequencing analysis of genomic DNA shows IGF1R c.641-2A>G (het) mutation within intron 2, and sequencing of IGF1R cDNA from probands (P1 and P2) and unaffected wild-type (WT) family members confirms that this causes an abnormal splicing event, leading to skipping of exon 3 in the probands. IGF1R, insulin-like growth factor 1 receptor.

Fig. 4.

IGF1R c.641-2A>G (het) mutation induces skipping of exon 3. Targeted Sanger sequencing analysis of genomic DNA shows IGF1R c.641-2A>G (het) mutation within intron 2, and sequencing of IGF1R cDNA from probands (P1 and P2) and unaffected wild-type (WT) family members confirms that this causes an abnormal splicing event, leading to skipping of exon 3 in the probands. IGF1R, insulin-like growth factor 1 receptor.

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Fig. 5.

IGF1R c.641-2A>G (het) mutation induces premature stop codon disrupting ligand binding and membrane attachment. a Linear depiction of domains of the IGF1R (αβ)2 homodimer with the cell membrane shown as the gray horizontal block. Location of IGF1R frameshift denoted by a black horizontal dashed line. b Three-dimensional model of wild-type (WT) IGF1R complexed with IGF1. The 2 IGF1-binding sites per αβ dimer include (1) parts of the L1 and α-CT domains from different subunits and (2) parts of Fn1 and Fn2 domains from the same subunit. c Three-dimensional model of IGF1R p.Met214Thrfs*67. Dashed lines are indicative of domains past the predicted stop codon, which would not be translated from the IGF1R c.641-2A>G allele. The two IGF1 binding sites on each αβ dimer are predicted to be disrupted. Figure modified from Kavran et al. [35]. IGF1, insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor.

Fig. 5.

IGF1R c.641-2A>G (het) mutation induces premature stop codon disrupting ligand binding and membrane attachment. a Linear depiction of domains of the IGF1R (αβ)2 homodimer with the cell membrane shown as the gray horizontal block. Location of IGF1R frameshift denoted by a black horizontal dashed line. b Three-dimensional model of wild-type (WT) IGF1R complexed with IGF1. The 2 IGF1-binding sites per αβ dimer include (1) parts of the L1 and α-CT domains from different subunits and (2) parts of Fn1 and Fn2 domains from the same subunit. c Three-dimensional model of IGF1R p.Met214Thrfs*67. Dashed lines are indicative of domains past the predicted stop codon, which would not be translated from the IGF1R c.641-2A>G allele. The two IGF1 binding sites on each αβ dimer are predicted to be disrupted. Figure modified from Kavran et al. [35]. IGF1, insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor.

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IGF1R Protein Expression Is Decreased in IGF1R c.641-2A>G Het Subject PBMCs

We assessed levels of IGF1R protein expression in affected family members compared to age- and sex-matched subjects (online suppl. Table. 1). IGF1R expression has previously been observed at lower levels in bulk PBMCs of subjects with IGF1R mutations using flow cytometry [26, 27]. The IGF1R c.641-2A>G (IGF1RHet) subjects, including the rhGH-treated twins, showed significantly lower IGF1R expression on PBMCs, at 50 ± 8% of control levels (Fig. 6), suggestive of haploinsufficiency. Here, we also used forward and side-scatter characteristics to gate on granulocytes, monocytes, and lymphocytes in order to understand which PBMC populations showed reduced IGF1R expression in the IGF1RHet subjects. IGF1R expression was significantly reduced in the IGF1RHet subjects as compared to controls, throughout all PBMC subpopulations analyzed, to the following proportions of levels observed in controls: 40 ± 4% in granulocytes, 55 ± 7% in monocytes, and 69 ± 15% in lymphocytes (Fig. 6), indicating a global defect in IGF1R expression.

Fig. 6.

IGF1R protein expression is significantly reduced on PBMCs of IGF1RHet subjects. Whole blood staining was performed to assess IGF1R levels via flow cytometry. a Representative histograms of CD221 (IGF1R) expression on bulk PBMC, granulocyte, monocyte, and lymphocyte populations based on size and granularity of an age- and sex-matched control (black) as compared to an IGF1RHet subject (gray). b Geometric mean fluorescence intensity (gMFI) of CD221 is significantly reduced on IGF1RHet PBMCs, granulocytes, monocytes, and lymphocytes. Twins (circles), older sister (triangles), and mother (squares) shown with their respective age-matched controls distinguished by shape. Mann-Whitney test: *p < 0.05; **p < 0.01. IGF1RHet subjects, insulin-like growth factor 1 receptor heterozygous subjects; PBMCs, peripheral blood mononuclear cells.

Fig. 6.

IGF1R protein expression is significantly reduced on PBMCs of IGF1RHet subjects. Whole blood staining was performed to assess IGF1R levels via flow cytometry. a Representative histograms of CD221 (IGF1R) expression on bulk PBMC, granulocyte, monocyte, and lymphocyte populations based on size and granularity of an age- and sex-matched control (black) as compared to an IGF1RHet subject (gray). b Geometric mean fluorescence intensity (gMFI) of CD221 is significantly reduced on IGF1RHet PBMCs, granulocytes, monocytes, and lymphocytes. Twins (circles), older sister (triangles), and mother (squares) shown with their respective age-matched controls distinguished by shape. Mann-Whitney test: *p < 0.05; **p < 0.01. IGF1RHet subjects, insulin-like growth factor 1 receptor heterozygous subjects; PBMCs, peripheral blood mononuclear cells.

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IGF1R c.641-2A>G Het Subjects Show Altered CD4+ T-Cell Skewing

We postulated that IGF1R haploinsufficiency, evident in PBMCs, might impact immune function [25] in the IGF1RHet subjects. Flow cytometric immunophenotyping was performed on peripheral blood to measure major subsets of CD4+ and CD8+ T cells, effector CD4+ T cells (Teff), CD4+ regulatory T cells, follicular helper T cells, B cells, natural killer cells, dendritic cells, and monocytes. The immune profiles of the IGF1RHet subjects were quite similar to those of controls, with the exception of Teff populations (Fig. 7a; online suppl. Tables 2, 6). Here, IGF1RHet subjects showed significantly lower percentages of CD4+CD45RO+CD183CD196+ T-helper 17 (Th17) cells and significantly higher percentages of CD4+CD45RO+CD183+CD196- T-helper 1 (Th1) cells than age- and sex-matched controls (Fig. 7b, c), suggesting a shift in the effector CD4+ T-cell phenotype. Despite the rhGH-induced IGF1 upregulation in the twin probands (Fig. 1a), Teff phenotypes were similar between all IGF1RHet subjects (Fig. 7b, c).

Fig. 7.

Broad immunophenotyping reveals modulation of CD4+ T-cell skewing in IGF1RHet subjects. Whole blood was analyzed for percentages of subpopulations of naïve and memory CD4+ and CD8+ T cells (circles), effector CD4+ T cells (triangles), regulatory T cells (squares), follicular helper T cells (diamonds), naïve and memory B cells (inverted triangles), natural killer cells, dendritic cells, and monocytes (circles with crosses). For more detail on the populations analyzed, see online suppl. Table 2 and online suppl. Figures 2–4. a Volcano plot of immune phenotypes in control versus IGF1RHet subjects reveals that Th1 (CD3+CD4+CD45RO+CD183+CD196) cells were significantly decreased and Th17 (CD3+CD4+CD45RO+CD183CD196+) cells were significantly increased in whole blood of controls as compared to IGF1RHet subjects. Multiple t tests were performed with a significance threshold of p = 0.05 (horizontal dashed line). b Representative gating of CD196 and CD183 on CD3+CD4+CD45RO+ cells from a control and an IGF1RHet subject. c While the percentages of Th2 (CD183CD196) and Th1/17 (CD183+CD196+) were not altered, Th17 (CD183CD196+) cells were significantly decreased and Th1 (CD183+CD196) cells were significantly increased in IGF1RHet subjects. Twins (circles), older sister (triangles), and mother (squares) shown with their respective age-matched controls distinguished by shape. Mann-Whitney test: *p < 0.05; **p < 0.01. IGF1RHet subjects, insulin-like growth factor 1 receptor heterozygous subjects; Teff, effector CD4+ T cells; Treg, CD4+ regulatory T cells; Tfh, follicular helper T cells; NK, natural killer cells, DC, dendritic cells.

Fig. 7.

Broad immunophenotyping reveals modulation of CD4+ T-cell skewing in IGF1RHet subjects. Whole blood was analyzed for percentages of subpopulations of naïve and memory CD4+ and CD8+ T cells (circles), effector CD4+ T cells (triangles), regulatory T cells (squares), follicular helper T cells (diamonds), naïve and memory B cells (inverted triangles), natural killer cells, dendritic cells, and monocytes (circles with crosses). For more detail on the populations analyzed, see online suppl. Table 2 and online suppl. Figures 2–4. a Volcano plot of immune phenotypes in control versus IGF1RHet subjects reveals that Th1 (CD3+CD4+CD45RO+CD183+CD196) cells were significantly decreased and Th17 (CD3+CD4+CD45RO+CD183CD196+) cells were significantly increased in whole blood of controls as compared to IGF1RHet subjects. Multiple t tests were performed with a significance threshold of p = 0.05 (horizontal dashed line). b Representative gating of CD196 and CD183 on CD3+CD4+CD45RO+ cells from a control and an IGF1RHet subject. c While the percentages of Th2 (CD183CD196) and Th1/17 (CD183+CD196+) were not altered, Th17 (CD183CD196+) cells were significantly decreased and Th1 (CD183+CD196) cells were significantly increased in IGF1RHet subjects. Twins (circles), older sister (triangles), and mother (squares) shown with their respective age-matched controls distinguished by shape. Mann-Whitney test: *p < 0.05; **p < 0.01. IGF1RHet subjects, insulin-like growth factor 1 receptor heterozygous subjects; Teff, effector CD4+ T cells; Treg, CD4+ regulatory T cells; Tfh, follicular helper T cells; NK, natural killer cells, DC, dendritic cells.

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We report a novel variant, IGF1R c.641-2A>G, which leads to premature protein termination and reduced IGF1R protein surface expression. Haploinsufficiency resulted in variable expressivity in this family affected by a splice site mutation in the IGF1R gene. Associated hypoglycemia was found even in family members less affected by short stature and poor growth. In the twin probands most affected, their growth responded to supratherapeutic exogenous rhGH administration, and all 3 affected children had improvement in hypoglycemia with dietary cornstarch administration.

The risk of hypoglycemia in these patients with the IGF1R c.641-2A>G mutation is likely multifactorial. IGF1 levels were in the mid to upper half of the normal reference range for age for all 3 affected children at baseline screening, and hypoglycemia occurred before and after rhGH-induced supraphysiologic increases in IGF1 levels in the twin probands, similar to the pattern of hypoglycemic events observed in another heterozygous IGF1R mutation [24]. It is known that a 50% loss of IGF1R expression increases insulin sensitivity, as supported by elevated insulin-induced AKT activation in a previously characterized IGF1R mutation [8]. Increased hybrid IGF1R and IR heterodimers may also contribute to hypoglycemia due to increased blood glucose uptake from IGF1 binding as compared to IGF1R homodimers. Future studies should address whether similar mechanisms occur in those affected by IGF1R c.641-2A>G to promote hypoglycemia. IGF1-induced glucose uptake is reported to be no greater than 6% of insulin’s capacity [36], but IGF1 can be found at concentrations 100× higher than insulin in plasma concentration. These effects may be exacerbated if the bioavailability of IGF1 is increased, as would be expected in the case of suppression of IGFBP-1 levels in the setting of mild hypoglycemia for the older sibling of the twin probands. IGF1 also suppresses GH and hepatic glucose production [37, 38], leading to decreased counter-regulatory compensation for hypoglycemia during times of stress or low glycogen [24]. Administration of rhGH did not alleviate the hypoglycemia, and thus GH deficiency is not a contributor to their hypoglcemia. However, we speculate that supraphysiologic IGF1 levels from rhGH could bind to IGF1R-IR heterodimers or cross-bind with the IR (though at lower affinity than insulin binding). While glucose intolerance, rather than hypoglycemia [24], has been more frequently observed in subjects with other IGF1R mutations [13-15, 17, 23], it has been suggested that hypoglycemia in early life could evolve into glucose intolerance in later life as a consequence of β-cell apoptosis with the loss of prosurvival IGF1R signaling [39].

Decreased IGF1R protein expression has been previously reported in subjects with other heterozygous mutations in the IGF1R gene [3, 5, 7, 8, 12, 14, 24]. While most of these studies utilized fibroblasts to assess IGF1R expression, we confirmed that PBMCs may serve as an accessible source for the means of monitoring IGF1R expression in patients with short stature and suspected IGF1R mutations [26, 27]. We also extended beyond these previous studies [26, 27] to show that defective IGF1R expression could be observed throughout lymphocyte, monocyte, and granulocyte subpopulations.

Fibroblasts from subjects carrying IGF1R haploinsufficiency mutations have previously been shown to possess defects in IGF1-induced IGF1R signaling [3-5, 7-11, 14, 15, 17, 24], suggesting that decreased IGF1R protein expression directly correlated with reduced IGF1R signaling. However, in PBMCs, the role of IGF1R may be more complex as signaling appears to require simultaneous stimulation of the PI3K/Akt pathway through additional surface receptors, including but not limited to toll-like receptors or the T-cell receptors [40-42]. This confounded our ability to directly measure and compare IGF1R signaling between genetically diverse human subjects with variable responses to these secondary immune stimuli.

Broad immunophenotyping efforts revealed that IGF1R c.641-2A>G Het subjects show largely normal proportions of innate and adaptive immune populations. However, a significant shift in CD4+ Th-cell lineage commitment, with an increase in Th1 and a decrease in Th17 populations, was observed. These data are in agreement with studies suggesting that IGF1R signaling modulates CD4+ T-cell function by inhibiting Th1 skewing [43] and promoting Th17 skewing [44], both in vitro and in vivo [45]. Our interpretation of this immune phenotype resulting from impaired IGF1R signaling is potentially complicated by the supraphysiologic IGF1 levels induced by the twins’ rhGH treatment. Reassuringly, the mother and older sister were not treated with rhGH, suggesting that our observations in the family are likely reflective of the impact of the shared genetic mutation. Regardless, this immune phenotype should be assessed in subjects with other IGF1R haploinsufficiency mutations in order to verify that the phenotype is associated with hampered IGF1R expression.

While the classical role of Th1 cells is to drive immunity against intracellular pathogens and Th17 cells to protect against extracellular pathogens, these subsets play important roles in a wide variety of diseases including autoimmunity and cancer [46]. Although standardized normal reference ranges for Th1 and Th17 cells for age have yet to be developed [30], the modest shifts observed in CD4+ T-cell skewing in the IGF1R c.641-2A>G Het subjects are likely consistent with their lack of overt immune defects. However, the potential for similar IGF signaling-related shifts in Th1/Th17 ratios contributing to disease [47] in populations with underlying genetic risk should still be considered. The data presented herein illustrate a previously unreported heterozygous IGF1R mutation with variable clinical phenotype and demonstrate the novel concept of IGF1R haploinsufficiency potentially affecting immune function.

We thank Kieran McGrail and Krysten Floyd for their technical assistance with sample processing, biorepository management, and procurement of demographic data. Special thanks are extended to all study subjects and their families for generously participating. We thank the clinical staff for sample acquisition.

All procedures were approved by local Institutional Review Boards and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from participants (or their legal guardian in the case of minors) prior to enrollment.

The authors have no conflicts of interest to declare.

Project support was provided by grants from the National Institutes of Health (F31 DK117548 to M.R.S.; P01 AI42288 to T.M.B.; R21HD98417 to V.H.).

M.R.S. researched and analyzed the data in Figures 6 and 7 and wrote the manuscript; T.P.F. researched and analyzed the data in Figures 1 and 2 and wrote the manuscript; D.J.P. and J.A.M. researched the data in Figure 7 and reviewed/edited the manuscript; AM provided samples described in online suppl. Tables 1, 2 and reviewed/edited the manuscript; V.H., R.R., and A.D. researched and analyzed the data in Figures 3-5 and reviewed/edited the manuscript; T.M.B. and L.M.J. conceived the study and reviewed/edited the manuscript.

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Melanie R. Shapiro and Timothy P. Foster contributed equally as first authors.Todd M. Brusko and Laura M. Jacobsen contributed equally as senior authors.

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