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Hospital for Children and Adolescents (K.R., J.K., A.S., A.K., S.L., R.P., E.K., W.K.) and Institute for Laboratory Medicine and Molecular Diagnostics (J.K.), University of Leipzig, 04109 Leipzig, Germany; and Rhode Island Hospital, Brown University Medical School (R.S.), Providence, Rhode Island 02912
Address all correspondence and requests for reprints to: Dr. Klemens Raile, Pediatric Endocrinology and Diabetes, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, D-13353 Berlin, Germany. E-mail: klemens.raile{at}charite.de.
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Abstract |
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Objective: We studied clinical and in vitro aspects of a human IGF1R gene dosage effect. We provide detailed clinical data on the two half-brothers and their mother with the Arg59Ter mutation. Arg59Ter and control fibroblasts were examined for functionality of IGF-I and insulin-stimulated receptor phosphorylation and signal transduction.
Results: The two brothers presented with primary microcephaly, mild mental retardation, and intrauterine as well as postnatal growth deficits. After GH therapy (30 µg/kg·d) for 24 months, the growth deficit in the propositus decreased by +1.0 SD. There was no clinical evidence for impaired glucose tolerance or hypoglycemia in all Arg59Ter subjects. In vitro, IGF-IR-deficient Arg59Ter cells expressed less IGF-IR and unchanged insulin receptor (IR) protein. Receptor autophosphorylation and phosphorylation of downstream protein kinase B/Akt exhibited resistance to IGF-I but showed an augmented response to insulin in Arg59Ter cells. Decreased IGF-IR content was accompanied by a reduction of IGF-IR/IR receptor hybrids, and therefore, increased levels of IR/IR homodimers probably explain increased insulin-stimulated receptor autophosphorylation and Akt phosphorylation.
Conclusions: In vivo and in vitro IGF-I resistance in Arg59Ter subjects and fibroblasts indicates a human IGF1R gene dosage effect involving not only the IGF-IR, but also IGF-IR/IR hybrids. The abundance of both the IGF-IR protein and IGF-IR/IR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunits containing the ligand-binding site and two intracellular ß-subunits with intrinsic tyrosine kinase activity (1). Each proreceptor peptide forms a disulfide-linked /ß-subunit complex, and these further associate by disulfide bonding into /ß-/ß tetramers as IGF-IR or IR homoreceptors and also as hybrid receptors composed of IGF-IR /ß and IR /ß hemireceptors. Such hybrid receptors are widely expressed in many mammalian tissues and cell types (2, 3). Hybrid receptors bind IGF-I with an affinity similar to that of the IGF-IR and insulin with much lower affinity than the IR (4, 5, 6). Distinct biological functions of the receptor types are still not clear; hybrid receptors may potentially contribute to insulin and IGF-I responses in target tissues (7).
We have recently reported on a mother and her two sons with a heterozygous IGF1R mutation. The common phenotype includes pre- and postnatal growth retardation, modestly impaired motor and mental development, and primary microcephaly associated with normal or increased IGF-I and IGF-binding protein-3 (IGFBP-3) serum levels (8). The IGF-IR mutation in exon 2 of one IGF-IR allele results in early termination of transcription after 59 amino acids (Arg59Ter). The truncated receptor protein, if expressed at all, would correspond to only a short N-terminal fragment of the IGF-IR -chain, which could not bind IGF-I or insert into the cell membrane. In fibroblasts and peripheral blood monocytes, biallelic expression of the mutant and wild-type IGF1R alleles has been demonstrated. It thus can be concluded that individuals with the Arg59Ter IGF1R mutation manifest the human phenotype of IGF1R haploinsufficiency (8).
Igf1r gene knockout experiments have shown a mild pre- and postnatal growth deficit in heterozygous knockout (Igf1r+/–) mice (9). Igf1r gene dosage effects on the growth of several tissues and organs, in addition to overall embryonic and postnatal growth, were demonstrated in clonal mouse strains with a spectrum of IGF-IR deficiency (10).
In children born small for gestational age (SGA), binding of IGF-I to erythrocytes was noted to be lower than in children of normal height and weight (11), and it was suggested that decreased IGF1R expression may contribute to the observed reduced growth. In recent years, SGA children have been treated with recombinant human GH (rhGH), and a number of studies have reported improvement of growth as long as GH treatment continued (12, 13). However, the growth response in SGA children is not as marked as that usually seen in children with GH deficiency, and whether this results from the occurrence of IGF-I resistance in a majority of SGA children is not clear.
In this study, we investigated patients and fibroblasts with a heterozygous Arg59Ter IGF1R mutation to define clinical and functional aspects of reduced IGF-IR expression in humans.
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Subjects and Methods |
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We have investigated features of an adult female and her two sons with an IGF1R mutation leading to heterozygous deactivation of one IGF1R allele. The older son was our index patient, and the family history has been described previously (8).
Case 1, older brother.
Phenotypic description at age 8.5 yr (after 24 months of rhGH treatment) is as follows: height 124.4 cm (–1.50 SD), weight 28.0 kg, body mass index 18.8 kg/m2 (+1.20 SD), head circumference 50.4 cm (SD –0.93), and upper to lower segment ratio 1.20. He displayed mild dysmorphic signs as previously reported (8). His mild developmental delay persisted; speech, social skills, and fine and coarse motor skills were delayed, but continuously progressing. He was placed in a special school because of learning handicaps. Endocrine investigations revealed normal or elevated IGF-I, IGFBP-3, and IGF-2 levels, as documented between 2 and 6.4 yr of age before GH treatment was initiated. GH secretion was decreased after arginine infusion (0.5 g/kg) and insulin-induced hypoglycemia, but was normal in response to GHRH (Table 1
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Case 3, mother. The mother was born SGA at term, with a birth weight of 2400 g (–2.6 SD). Her final height was 148.0 cm (–2.6 SD), and head circumference was 52 cm (–1.7 SD), but her growth pattern had not been documented. A single determination of plasma IGF-I was normal at adult age (+0.4 SD). She finished high school after 8 yr without a regular exam, which corresponds to approximately the level of special school education today.
Materials and methods
Clinical and molecular studies were performed after obtaining approval from the ethical committee of the Medical Faculty of University of Leipzig and written consent from the parents.
Auxology
Height measurements were obtained using a wall-mounted precision stadiometer. Short-term growth response from 9 wk before to 11 wk after the onset of rhGH therapy was assessed by knemometry (14). Bone age was determined using the Bailey-Pinot method.
Assays
Serum levels of IGF-I were measured after acid-ethanol extraction by our in-house competitive solid phase immunoassay with a sensitivity of less than 15 ng/ml and inter- and intraassay coefficients of variation (CVs) of less than 10% (15). Serum levels of IGFBP-3 were determined with a commercially available ELISA (Diagnostic Systems Laboratories, Inc., Sinsheim, Germany) with a sensitivity of less than 0.8 ng/ml and inter- and intraassay CVs less than 12%. For rhGH measurements, the sensitivity of the assay (AutoDELFIA, PerkinElmer, Brussels, Belgium) was 0.02 ng/ml; inter- and intraassay CVs were less than 3.4%.
In vitro studies
Arg59Ter fibroblasts were cultured from a forearm skin biopsy of the propositus, control fibroblasts of age- and sex-matched donors were purchased from the Human Genetic Mutant Cell Repository (Coriell Institute of Medical Research, Camden, NJ; GM 05565, GM 00498, and GM 05381). The cells were grown and cultured as previously described (8). For phosphorylation experiments, cells were seeded into 175-cm2 flasks in culture medium, kept serum free overnight, then stimulated with 0–100 ng/ml IGF-I or insulin for 10 min at 37 C. rhIGF-I and human insulin were donated by Pharmacia Biotech (Stockholm, Sweden).
Cell lysis, immunoblotting, and immunoprecipitation
Protein expression of IGF-IR and IR and ligand-induced phosphorylation of IGF-IR, IR, and the downstream signaling protein, Akt, were measured by Western blotting using specific antibodies. Cells were washed twice with ice-cold PBS, scraped in ice-cold lysis buffer, vortexed, and centrifuged (14,000 x g for 3 min at 4 C). Protein content was assayed using a DC protein assay kit (Bio-Rad Laboratories, Inc., Hercules, CA) with BSA type V (Sigma-Aldrich Corp., Taufkirchen, Germany) as a standard. Total protein extracts (10–50 µg) were resolved by SDS-PAGE [7.5–10% (vol/vol) bisacrylamide-acrylamide, 37.5:1], transferred to nitrocellulose membranes, and immunoblotted with specific antibodies or antisera, and secondary antibodies were identified using chemiluminescence blotting substrate (Supersignal, Pierce/Perbio, Bonn, Germany). Primary antibodies included polyclonal rabbit antisera (Cell Signaling Technology, Beverly, MA) against the phosphotyrosine1158 residue of human IGF-IR and IR (dilution, 1:500), Akt (1:1,000), and phospho-Ser473-Akt (1:1,000), plus polyclonal goat antisera from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA) against the IGF-IR ß-subunit (C-20; 1:2,000) and the insulin receptor ß-subunit (C19; 1:1,000). Highly specific monoclonal antibodies against the human IGF-IR -subunit (2C8; Santa Cruz Biotechnology, Inc.) and the IR ß-subunit (29B4; Santa Cruz Biotechnology, Inc.) with no cross-reactivity for IR or IGF-IR, respectively, were used for immunoprecipitation. Primary rabbit antibodies were detected by goat antirabbit immunoserum (Pierce Chemical Co., Bonn, Germany) diluted 1:40,000, and primary goat antibodies were detected by rabbit antigoat immunoserum (DakoCytomation, Hamburg, Germany) diluted 1:40,000.
For immunoprecipitations, protein lysates were precleared with protein G. Approximately 500 µg protein was then incubated with the indicated specific antibodies (1.25 µl) bound to protein G agarose for 16 h at 4 C. Immune complexes were collected by centrifugation, washed in extraction buffer, solubilized, diluted in 2x Laemmli sample buffer, and analyzed as described in detail for Western blot analysis.
Data analysis
Density analysis of specific Western blot protein bands was performed with Image Beta 4.0.2 (Scion Corp., Frederick, MD). Statistical comparisons were carried out by unpaired Student’s t test with Welch’s correction for unequal variances where appropriate. Analysis and graphs were performed using GraphPad PRISM 3.0 software (GraphPad Software, Inc., San Diego, CA). Data are plotted as the mean and SD of the mean.
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Results |
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Common phenotypic characteristics of the two male children included prenatal and postnatal growth retardation, primary microcephaly, and mild facial dysmorphism characterized by a broad nasal bridge, broad and rounded nasal tip, long and smooth philtrum, thin upper lip, and an inverted, fleshy lower lip. Both individuals had short broad fingers, short distal phalanges, and bilateral clinodactyly. The body length of the propositus (III/1) was reduced at birth and remained retarded (–2.8 to –3.52 SD; Fig. 1A). Starting at 5–6 yr, mild catch-up growth was evident, which was accelerated during the first 2 yr of GH treatment. Body weight was markedly decreased until 3 yr of age and continuously increased thereafter (Fig. 1B). Head size exhibited a specific growth pattern, with primary microcephaly and further deviations below normative percentiles during the first 6 yr, followed by accelerated increase to above the third percentile by the age of 7 yr (Fig. 1C). This unusual increase in head size during GH treatment was not associated with any cerebral pathology indicating hydrocephalus or cerebral edema. The younger male (III/2) bearing the IGF1R mutation was born SGA, grew below the third percentile, and also has microcephaly. He followed growth patterns similar to those of his older brother, but, in general, all growth deficits were less marked (Fig. 1, right panels).
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Because primary microcephaly, defined as decreased prenatal head size, is likely to be generated by reduced brain size, neuromotor and psychosocial functions were evaluated in both male children and were found to be delayed. Generalized muscular weakness was evident from the newborn period, although suckling and oral feeding continued to be sufficient. The older individual has been continuously followed by developmental neurologists, and he has ongoing treatment from speech and occupational therapists. His gross motor coordination and fine motor dexterity were delayed, e.g. walking starting at 20 months, and a developmental delay of approximately 10 months was evident at 6 yr. Language dysfunction was predominantly identified as spelling disorder. Magnetic resonance brain imaging was normal at age 5 yr with no abnormalities in structure or size of brain and pituitary. The younger male child was considered to have significant generalized muscle weakness until the age of 6 months, but his gross motor milestones were within the normal range. He developed speech and fine motor skills with mild delay.
Changes in linear growth, body weight, and glucose metabolism during rhGH therapy
Because of persistent growth below –2.5 SD, the older male child was treated with rhGH. Considerations were, first, that high GH serum levels might promote growth through direct action on target tissues via the GH receptor, and second, that high local and systemic IGF-I levels created by GH treatment might overcome relative IGF-I resistance. During therapy with rhGH at a daily dose of 30 µg/kg·d, growth velocity markedly increased within the first 3 months, as documented by knemometry and height velocity (Table 2). Height SD values increased progressively from –2.51 to –1.93 SD after 1 yr and –1.50 SD after 2 yr of GH therapy. The increase in body weight was variable during the first 6 months, but subsequently there was a progressive increase in body weight (Fig. 1B
and Table 2). Bone age was approximately 1 yr delayed at the start of GH treatment and was appropriate for chronological age after 2 yr of GH. Oral glucose tolerance testing with 1.75 g/kg performed before GH treatment and annually during rhGH therapy demonstrated normal glucose tolerance, but homeostasis model assessment of insulin resistance was mildly elevated in two of three glucose/insulin samples, with a homeostasis model assessment of insulin resistance above the 95th percentile compared with normal values from 9-yr-old Canadian boys (16) (Table 2).
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To determine the impact of decreased IGF-IR expression on IGF-I signaling, IGF-IR abundance, IGF-IR phosphorylation, and IGF-I-dependent Akt phosphorylation were assessed by Western blotting. Fibroblasts obtained from the propositus expressed significantly lower levels of IGF-IR ß-subunit (Fig. 2A). IGF-I-stimulated phosphorylation of IGF-IR in Arg59Ter and three control cell lines was stimulated in a dose-dependent fashion, but the patient’s cells needed approximately 10-fold higher IGF-I concentrations to achieve equal levels of Tyr-phosphorylated IGF-IR compared with controls. In contrast, after normalization to IGF-IR levels, no significant difference was found between Arg59Ter and control cells (Fig. 2B). Furthermore, phosphorylation of Akt, a downstream signaling intermediate of the IGF-I receptor pathway, was stimulated by IGF-I in a dose-dependent fashion, but Akt phosphorylation in Arg59Ter cells also needed approximately 10-fold higher IGF-I concentrations than control fibroblasts despite equal amounts of total Akt protein (Fig. 2C).
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To examine whether lower expression of the IGF-IR would alter insulin signaling, Arg59Ter fibroblasts and control cells were exposed to increasing concentrations of insulin and immunoblotted with IGF-IR, IR, Akt, and phospho-Akt antibodies. Interestingly, dose-dependent stimulation with insulin resulted in higher, dose-dependent Akt phosphorylation in the IGF-IR-deficient Arg59Ter fibroblasts compared with control cell lines despite comparable levels of total IR and Akt protein expression (Fig. 3A). Because IR/IGF-IR heterodimers bind insulin with lower affinity than IR/IR homodimers, we investigated the possibility that lower expression of IGF-IR in Arg59Ter fibroblasts would sequester fewer IR into IR/IGF-IR hybrids. For this purpose, protein lysates of Arg59Ter and control fibroblasts were immunoprecipitated with antibodies specific for the IGF-IR ß-subunit or IR ß-subunit. The resulting immunoprecipitates then were resolved by SDS-PAGE and immunoblotted with both IGF-IR and IR antibodies. Compared with two control cell lines, Arg59Ter cells demonstrated markedly decreased IR protein in IGF-IR antibody immunoprecipitates (Fig. 4A). Similarly, decreased IGF-IR were identified in immunoblots of IR antibody immunoprecipitates from Arg59Ter compared with control fibroblasts (Fig. 4, B and C). The presence of decreased IR coprecipitated with IGF-IR confirmed decreased hybrid receptor formation of the Arg59Ter cells. In the presence of equal expression of total IR protein, but decreased IR/IGF-IR hybrids, increased levels of IR/IR homodimers are likely in Arg59Ter cells.
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Discussion |
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qter syndrome resulting in haploinsufficiency of the IGF1R gene (17, 18, 19, 20). Common phenotypic features of these children include intrauterine growth retardation, postnatal growth failure, microcephaly, facial abnormalities (high arched palate, abnormal ears, and hypertelorism), skeletal abnormalities (clinodactyly, club feet, and scoliosis), and mental retardation. In vitro, fibroblasts from patients with partial 15q26.1qter monosomy display decreased IGF-I ligand binding and IGF-IR tyrosine kinase activation, whereas those from trisomy 15q26.1qter patients display increased IGF-IR phosphorylation (17, 21). These data are consistent with an IGF-IR gene dosage effect of the human IGF1R gene, but leave unresolved the role of the IGF1R vs. other genes within the affected region of chromosome 15. Comparing 15q26.1qter and Arg59Ter subjects who also lack one functional IGF1R allele, prenatal and postnatal growth retardation, microcephaly, and mental retardation are common features, but skeletal abnormalities are more severe in 15q26.1qter subjects and therefore may not be dependent on IGF-IR deletion.
Four different human IGF1R mutations have been reported to date, each of which highlights distinct aspects of IGF-IR function. The heterozygous Arg59Ter mutation results in inactivation of one IGF1R allele and a consequent decrease in mRNA and protein expression of the intact IGF-IR (8). The compound heterozygous IGF1R mutations Arg108Gln/Lys115Asn, with each mutation changing binding characteristics of the IGF-I-binding pocket within the -subunit, results in decreased IGF-I binding affinity and receptor phosphorylation (8). A recently reported heterozygous mutation, Arg709Gln, affects the cleavage site between - and ß-subunits, resulting in intracellular sequestration of unprocessed proreceptor and decreased expression of fully cleaved and processed IGF-IR (22). Most recently, a patient with a heterozygous mutation Glu1050Lys within the IGF-IR tyrosine kinase domain, with reduced autophosphorylation of the IGF-IR tyrosine kinase and reduced postreceptor signaling, was reported (23). In subjects with these mutations, common features are intrauterine growth retardation and lack of postnatal catch-up growth. The degrees of psychomotor delay and microcephaly are more variable, but some developmental abnormality has been reported in all individuals. Complete deletion of the IGF1R has not been observed in humans and thus may be lethal, even though Igf1r–/– mice have been identified, but die after birth (24).
IGF-I levels in subjects with IGF1R mutations were either normal or elevated to an extent that does not support normal postnatal growth. The highest IGF-I levels were observed in the girl with the heterozygous compound Arg108Gln/Lys115Arg mutations that resulted in markedly decreased IGF-I binding affinity (8), whereas in our study, IGF-I levels were elevated in the more severely affected older child, but were normal in his less markedly growth-restricted younger brother. GH treatment in the older child induced IGF-I serum levels that were higher than that and a growth response that was comparable to that normally observed in SGA patients treated with comparable doses of GH (25, 26, 27). Functionally, higher IGF-I may have resulted from decreased receptor-mediated clearance of IGF-I, and the adequate growth response for the most part reflected the extent of activation of reduced number of IGF-I receptors by these high IGF-I concentrations.
At the cellular level, functional studies in Arg59Ter fibroblasts demonstrated enhanced insulin-dependent IR autophosphorylation and Akt phosphorylation in Arg59Ter fibroblasts despite unchanged IR abundance compared with control cells. If IGF-I and insulin signaling are completely independent from each other, insulin signaling should not be influenced by decreased IGF-IR expression. Studies in fibroblasts from Igf1r-knockout mice (R–) overexpressing IGF-IR and IR demonstrated that hybrid receptors predominantly bind IGF-I, whereas IR and IGF-IR homodimers bind their respective ligands with high affinity (4, 28, 29). In a more recent study, IGF-I was found to induce weak, but significant, phosphorylation of IR, whereas insulin was not able to activate the IGF-IR. This effect was attributed to IR/IGF-IR hybrid signaling activated by IGF-I (4). Together, these findings as well as those from other studies (6) support the conclusion that IGF-IR/IR hybrid receptors exhibit high affinity IGF-I binding and low affinity insulin binding. Therefore, increased levels of IR/IR homodimers as a consequence of decreased IR being sequestered into IR/IGF-IR hybrids probably explain the higher insulin-stimulated receptor autophosphorylation and Akt phosphorylation found in Arg59Ter cells.
The clinical relevance of IGF-IR/IR hybrid receptors vs. IR/IR homodimer signaling was demonstrated in muscle extracts of obese subjects with insulin resistance and hyperinsulinemia, and a causal link was postulated between IGF-IR/IR hybrid formation and insulin resistance in these subjects (30, 31). Furthermore, high glucose concentrations were found to up-regulate muscle hybrid receptors, and this mechanism was suggested to be of clinical relevance in insulin-resistant and diabetic patients. Nevertheless and despite the increased insulin sensitivity in IGF-IR-depleted Arg59Ter fibroblasts in vitro, we did not observe increased or clearly decreased insulin sensitivity in Arg59Ter subjects. Additional studies will be required of additional patients with IGF-IR defects to establish the relationships between IGF-IR abundance and insulin sensitivity in vivo.
In conclusion, the Arg59Ter IGF1R mutation results in a phenotype characterized by pre- and postnatal growth retardation, microcephaly, and mental retardation. The Arg59Ter subjects share phenotypic similarities with other reported cases of IGF1R mutations, monosomy 15qter, and also mice with Igf1r inactivation. The variability of specific clinical features in individuals with different IGF1R mutations may be related to specific functions of mutated IGF-IR regions or, alternatively, to variations in genetic background. Fibroblasts from the Arg59Ter propositus studied in vitro exhibited decreased IGF-IR abundance and IGF-I resistance, as assessed by IGF-IR phosphorylation and postreceptor signal transduction. The Arg59Ter fibroblasts also manifested an increased signaling response to insulin, which is probably caused by decreased formation of IGF-IR/IR hybrids, resulting in a higher proportion of IR present as highly insulin-sensitive IR/IR homodimers. Therefore, IGF-IR expression has a strong impact on insulin signaling, and IGF-IR and IR are strongly interactive through the formation of hybrid receptors.
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Footnotes |
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K.R., J.K., A.S., A.K., S.L., R.S., R.P., J.K., E.K., and W.K. have nothing to declare.
First Published Online March 28, 2006
Abbreviations: CV, Coefficient of variation; IGF-BP, IGF-binding protein; IGF-IR, IGF-I receptor; IR, insulin receptor; rhGH, recombinant human GH; SGA, small for gestational age.
Received September 27, 2005.
Accepted March 17, 2006.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, Respective bone ages.
