* 147370

INSULIN-LIKE GROWTH FACTOR I RECEPTOR; IGF1R


HGNC Approved Gene Symbol: IGF1R

Cytogenetic location: 15q26.3     Genomic coordinates (GRCh38): 15:98,648,539-98,964,530 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q26.3 Insulin-like growth factor I, resistance to 270450 AD, AR 3

TEXT

Cloning and Expression

Flier et al. (1986) studied a monoclonal antibody to the receptor for type I insulin-like growth factor (IGF1; 147440).

Ullrich et al. (1986) determined the complete primary structure of the receptor for IGF I from cloned cDNA. The deduced sequence predicts a 1,367-amino acid receptor precursor, including a 30-residue signal peptide, which is removed during translocation of the nascent polypeptide chain. Cleavage of the precursor generates alpha and beta subunits as in the case of the insulin receptor (INSR; 147670).

Using an in vitro self-selection technique, Salehi-Ashtiani et al. (2006) identified a self-cleaving ribozyme associated with the IGF1R gene.


Biochemical Features

Crystal Structure

Lou et al. (2006) reported the crystal structure of the first 3 domains of INSR at 2.3-angstrom resolution and compared it with the structure of the corresponding fragment of IGF1R. They observed notable differences in the regions governing ligand specificity and binding.


Gene Structure

Abbott et al. (1992) determined that the IGF1R gene contains 21 exons and spans about 100 kb. Cooke et al. (1991) analyzed the promoter region and found that the 5-prime flanking and untranslated region is GC-rich and contains numerous potential SP1 and AP2 binding sites as well as a thyroid response element, but no TATA or CCAAT elements.


Mapping

Francke et al. (1986) assigned the IGF1R locus to 15q25-q26 by use of a DNA probe in somatic cell hybrids and for in situ hybridization. Most grains in the latter experiments were in distal q26.

Roback et al. (1991) localized the IGF1R gene distal to chromosome 15q26.1 based on findings from a patient with a 15q26.1-qter deletion and monozygosity for IGF1R.

With a method that combined PCR and single-strand conformation polymorphism (SSCP) analysis for identifying polymorphisms in the 3-prime untranslated regions of genes, Poduslo et al. (1991) identified an insertion/deletion polymorphism of the IGF1R gene and corroborated localization to chromosome 15q25-q26.

Gross (2021) mapped the IGF1R gene to chromosome 15q26.3 based on an alignment of the IGF1R sequence (GenBank BC113610) with the genomic sequence (GRCh38).


Gene Function

Prager et al. (1992) showed that a mutant human IGF-I receptor interfered with the expected suppression of growth hormone in cultured rat pituitary cells, thus demonstrating a dominant-negative phenotype. (The 'dominant-negative' concept was first clearly articulated by Herskowitz (1987). He recognized 2 classes. The first class comprises multimeric proteins dependent on oligomerization for activity; the presence in a multimer of a mutant subunit with intact binding but altered catalytic domains can abrogate the function of the entire multimer. The second class involves monomeric proteins, in which dominant-negative mutations can occur if substrate is limiting; a mutant able to bind the substrate but not metabolize it would have this effect.)

Using a yeast 2-hybrid system, Dey et al. (1998) identified a regulatory subunit of phosphatidylinositol (PI) 3-kinase, PIK3R3 (606076), as a binding partner of IGF1R. They concluded that the SH2 domain of PIK3R3 interacts with IGF1R and INSR in a kinase-dependent manner, providing an alternative pathway for the activation of PI 3-kinase by these 2 receptors.

Rotem-Yehudar et al. (2001) found evidence that IGF1R associated with SNAP29 (604202), a synaptosomal-associated protein, and with EHD1 (605888), a protein containing motifs important for protein-protein interaction and for intracellular sorting. Through immunoprecipitation of rat tissues, they found that SNAP29 and EHD1 are present in complexes with IGF1R. They also found that IGF1 induction of EHD1-transfected CHO cells results in intracellular colocalization of EHD1 and IGF1R.

In 15 informative patients with embryonal tumors (Wilms tumor, hepatoblastoma, and adrenal tumors), Howard et al. (1993) examined IGF1R gene expression for evidence of imprinting. All but one sample of normal juvenile kidney and liver and associated tumors showed biallelic expression, suggesting that the human gene is not normally imprinted as it is in the mouse, where both Igf1r and Igf2r are imprinted. The exception in the study of Howard et al. (1993) was a patient with Beckwith-Wiedemann syndrome (130650) in which monoallelic expression of the maternally derived IGF1R allele was found in normal kidney, associated Wilms tumor, and peripheral blood lymphocytes. By demonstrating biallelic expression, Ogawa et al. (1993) likewise showed that both the IGF1R and IGF2R (147280) genes are expressed equally from the maternal and paternal alleles in human tissues.

The insulin-like growth factor I receptor plays a critical role in transformation events. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. The p53 gene (191170), the most frequently mutated gene in human cancer, is a nuclear transcription factor that blocks cell cycle progression and induces apoptosis. Werner et al. (1996) reported results of experiments that indicated that mutant p53 proteins have a stimulatory effect on promoter activity, whereas wildtype p53 suppresses the activity of the IGF1R promoter. These effects of p53 seemed to involve its interaction with components of the basal transcription machinery. Due to the central role of IGF1R in cell cycle progression and transformation, derepression of IGF1R promoter by mutant p53 may constitute an important paradigm in tumorigenesis. (Most of the cancer-related mutations of p53 occur in the central domain of the p53 molecule.)

Maor et al. (2000) cotransfected a luciferase reporter gene under the control of the IGF1R promoter with a wildtype BRCA1 (113705)-encoding expression vector into multiple cell lines. They observed a significant reduction in luciferase activity in all 3 cell lines tested, demonstrating suppression of promoter activity by BRCA1 in a dose-dependent manner. Functional interaction between BRCA1 and SP1 (189906) in the regulation of the IGF1R gene was studied in Schneider cells, a Drosophila cell line which lacks endogenous SP1. In these cells, BRCA1 suppressed 45% of the SP1-induced trans-activation of the IGF1R promoter. Maor et al. (2000) concluded that BRCA1 is capable of suppressing the IGF1R promoter in a number of cell lines, resulting in low levels of receptor mRNA protein. Maor et al. (2000) hypothesized that mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF1R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may elicit a myogenic event which may be a key mechanism in the etiology of breast and ovarian cancer.

Stromal cells derived from benign prostatic hyperplasia (600082) synthesize and secrete measurable levels of insulin-like growth factors I and II (IGF2; 147470). Grant et al. (1998) used RT-PCR analysis to demonstrate that the genes for both the type I receptor and the type II receptor are expressed by benign stromal cells in vitro. Incubation with the IGF1R-neutralizing antibody alpha-IR3 (50 microg/mL) reduced the rate of stromal cell proliferation by approximately 60 to 80%, even in the presence of stimulatory concentrations of IGF. Camptothecin-induced apoptosis was inhibited by the addition of IGF1 and IGF2 (500 ng/mL). The authors concluded that IGF1R is a pivotal molecule in prostatic stromal cell maintenance and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.

All-Ericsson et al. (2002) investigated the expression of IGF1R, focusing on its role in cell growth in uveal melanoma (155720). Their data suggested a significant association between high IGF1R expression and death due to metastatic disease. Because IGF1R is produced mainly in the liver, the preferential site for uveal melanoma metastases, these results pointed to the possibility of interfering therapeutically with IGF1R in uveal melanoma that appears to follow an aggressive clinical course.

Lambooij et al. (2003) demonstrated that IGF1 and IGF1R were present in capillary endothelial cells, retinal pigment epithelial cells, and fibroblast-like cells in choroidal neovascular membranes of age-related macular degeneration (see 153800).

Self-renewal and multi-lineage developmental potential define the unique properties of stem cells. In vivo, these properties are not autonomously achieved, and evidence points to a level of external control from the microenvironment. Bendall et al. (2007) demonstrated that these 2 properties depend on a dynamic interplay between human embryonic stem (ES) cells and autologously derived human ES cell fibroblast-like cells (hdFs). Both ES cells and hdFs are defined by dependence on insulin-like growth factor (IGF) and fibroblast growth factor (FGF). IGF1R expression was exclusive to the human ES cells, whereas FGFR1 (136350) expression was restricted to the surrounding hdFs. Blocking the IGF-II/IGF1R pathway reduced survival and clonogenicity of human ES cells, whereas inhibition of the FGF pathway indirectly caused differentiation. IGF-II is expressed by hdFs in response to FGF, and alone was sufficient in maintaining ES cell cultures. This study demonstrated a direct role of the IGF-II/IGF1R axis on human ES cell physiology and established that hdFs produced by human ES cells themselves define the stem cell niche of pluripotent human stem cells.

Giovannone et al. (2003) found that a fragment of mouse Gigyf1 (612064) containing the GYF domain bound Grb10 (601523) in mouse fibroblasts expressing Igf1r in the basal state. Stimulation with Igf1 resulted in increased binding of Gigyf1 to Grb10 and transient binding of Gigyf1 and Grb10 to Igf1r, presumably via the adaptor function of Grb10. At later time points, Gigyf1 dissociated, but Grb10 remained linked to Igf1r. Overexpression of the Grb10-binding fragment of Gigyf1 resulted in a significant increase in Igf1-stimulated Igf1r tyrosine phosphorylation. Giovannone et al. (2003) concluded that GRB10 and GIGYF1 may act cooperatively to regulate IGF1R signaling.

Using PCR, Sun et al. (2014) identified IRAIN (619212), a long noncoding RNA (lncRNA) transcribed from the IGF1R gene locus in human leukemia cells. Further analysis showed that IRAIN transcription occurs antisense to IGF1R, originates from a promoter in IGF1R intron 1, and overlaps the promoter and exon 1 of IGF1R. Allelic expression analysis indicated that IRAIN is imprinted, with the paternal allele expressed and the maternal allele suppressed. IRAIN bound chromatin DNA in the IGF1R promoter region and in an intronic enhancer in leukemia KG-1 cells. Binding of IRAIN to these regions formed an intrachromosomal loop that likely allowed IRAIN to be actively involved in interaction of 2 remote regions of the IGF1R gene.

To gain insight into the biologic pathways associated with nuclear IGF1R action, Solomon-Zemler et al. (2019) conducted a mass spectrometry-based proteomic analysis that identified interactors of IGF1R in nucleus of both benign and malignant breast cells. Using a combination of coimmunoprecipitation and silencing assays, Solomon-Zemler et al. (2019) provided evidence of a complex, bidirectional interplay between nuclear IGF1R and the nucleolar protein NOM1 (611269), which functions in translation, cell growth, and proliferation. Inhibition of nuclear IGF1R translocation by dansylcadaverine, an inhibitor of clathrin-mediated endocytosis into the nucleus, reduced NOM1 levels in nuclei of MCF7 cells. On the other hand, IGF1R overexpression enhanced NOM1 levels in the nuclear fraction. NOM1 silencing led to a major increase in IGF1R biosynthesis. Solomon-Zemler et al. (2019) concluded that their results were consistent with a physiologically relevant interplay between the nuclear IGF1 signaling pathway and nucleolar protein NOM1.

Griffiths et al. (2020) showed a mechanism of RSV entry into cells in which outside-in signaling, involving binding of the prefusion RSV-F glycoprotein with IGF1R, triggers the activation of protein kinase C-zeta (PKC-zeta) (PRKCZ; 176982). This cellular signaling cascade recruits nucleolin (NCL; 164035) from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. Griffiths et al. (2020) found that inhibiting PKC-zeta activation prevented the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduced viral replication and pathology in RSV-infected mice.


Molecular Genetics

Involvement in Growth and Insulin-Related Phenotypes

Approximately 10% of infants with intrauterine growth retardation (IUGR) remain small. Abuzzahab et al. (2003) postulated that mutations in the IGF1R gene resulting in IGF1 resistance (IGF1RES; 270450) might underlie some cases of prenatal and postnatal growth failure. In a group of 42 patients with unexplained IUGR and subsequent short stature, they found a girl who was compound heterozygous for missense mutations in IGF1R (R108Q, 147370.0001 and K115N, 147370.0002). Fibroblasts cultured from the patient had decreased IGF1 receptor function, as compared with that in control fibroblasts. In a cohort of 50 children with short stature who had elevated circulating IGF1 concentrations, Abuzzahab et al. (2003) identified 1 boy with a heterozygous nonsense mutation (R59X; 147370.0003) in IGF1R that reduced the number of IGF1 receptors on fibroblasts. Both children had IUGR, poor postnatal growth, and mild developmental delay; the boy also exhibited dysmorphic features.

Kawashima et al. (2005) screened 24 Japanese patients with unexplained IUGR and short stature for mutations in the IGF1R gene and identified a girl who was heterozygous for a missense mutation (R709Q; 147370.0004). The mutation, which is located within the cleavage site and results in failure of processing of the precursor protein to mature IGF1R, was also present in the proband's affected mother.

In a 13.6-year-old Russian girl with IUGR and short stature and in her aunt who had short stature, Inagaki et al. (2007) identified heterozygosity for a missense mutation in the IGF1R gene (R481Q; 147370.0005).

In a Lebanese brother and sister with IUGR, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels, Fang et al. (2012) sequenced the IGF1 and IGF1R genes and identified compound heterozygosity for missense mutations in the IGF1R gene (E121K, 147370.0006 and E234K, 147370.0007). Their unaffected consanguineous parents were each heterozygous for 1 of the mutations.

In a 13.5-year-old girl, born of first-cousin Lebanese parents, who had severe IUGR, short stature, microcephaly, facial dysmorphism, reduced subcutaneous fat, mild developmental delay, and elevated IGF1 levels, Gannage-Yared et al. (2013) sequenced the IGF1 and IGF1R genes and identified homozygosity for a missense mutation in the IGF1R gene (R10L; 147370.0008), for which her unaffected parents were heterozygous.

In a 2-year-old Italian girl with severe IUGR, short stature, microcephaly, progeroid features, developmental delay, and elevated IGF1 levels, Prontera et al. (2015) identified homozygosity for a c.2201G-T transversion in the IGF1R gene (147370.0009), predicted to affect the splicing process. Her short-statured consanguineous parents were heterozygous for the mutation, as were both of her grandmothers, who had short stature and type 2 diabetes (125853).

Involvement in Longevity

Downregulation of the IGF1 pathway or IGF1 plasma levels has been associated with an increased life span (see 152430). Bonafe et al. (2003) tested the hypothesis that polymorphic variants of IGF1 response pathway genes, namely IGF1R (G/A, codon 1013), PIK3CB (602925) (T/C, -359 bp; A/G, -303 bp), IRS1 (147545) (G/A, codon 972), and FOXO1A (136533) (T/C, +97347 bp), play a role in systemic IGF1 regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF1R had low levels of free plasma IGF1 and were more represented among long-lived people. Moreover, genotype combinations at IGF1R and PIK3CB genes affect free IGF1 plasma levels and longevity. Genotype combinations of an A allele at the IGF1R locus and a T allele at the PIK3CB locus (A+/T+ subjects) affect IGF1 plasma levels (having A-/T- individuals the highest free IGF1 plasma levels), as well as longevity, and the proportion of A+/T+ subjects significantly increased among long-lived individuals.

Suh et al. (2008) studied biochemical, phenotypic, and genetic variation in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGF1 associated with smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1R genes showed overrepresentation of heterozygous mutations in the IGF1R gene among female centenarians relative to controls that were associated with high serum IGF1 levels and reduced activity of IGF1R as measured in transformed lymphocytes. Suh et al. (2008) concluded that genetic variations in IGF1R that alter the IGF signaling pathway may play a role in modulation of human life span.

Exclusion Studies

Rasmussen et al. (2000) considered the IGF1 and IGF1R genes as candidates for low birth weight, insulin resistance, and type 2 diabetes. In genomic DNA from probands of 82 Danish families with type II diabetes, they identified no mutations predicting changes in the amino acid sequences of the IGF1 or IGF1R genes, although several silent and intronic polymorphisms were identified. The authors concluded that variability in the coding regions of IGF1 and IGF1R does not associate with reduced birth weight, insulin sensitivity index, or type II diabetes in the Danish population.


Cytogenetics

Roback et al. (1991) described a patient with a chromosome 15q26.1-qter deletion (612626) and monozygosity for the IGF1R gene. Clinical features of the patient included intrauterine growth retardation (IUGR), microcephaly, micrognathia, renal anomalies, lung hypoplasia, and delayed growth and development. The authors reviewed the clinical findings in patients with similar chromosome 15 deletions and speculated that the loss of an IGF1R allele may be related to the severe IUGR and postnatal growth deficiency observed in their patient and other patients with distal 15q deletions.

Okubo et al. (2003) reported 2 children with altered numbers of IGF1R alleles who presented with abnormal growth. Case 1 was a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal, but karyotype analysis identified a deletion on 15q26.2, and a FISH study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and had rapid, early postnatal growth. He had a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A FISH study using the same probes showed 3 copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only 1 IGF1R allele showed slower growth, whereas cells from the subject with 3 IGF1R alleles showed accelerated growth compared with controls.

Walenkamp et al. (2008) reported a 15-year-old girl with heterozygous deletion of 15q26.2-qter, including the IGF1R gene, who had been small for gestational age and who showed persistent postnatal growth retardation, microcephaly, and elevated IGF1 levels. She had been treated with growth hormone since the age of 5 years, which resulted in a good growth response and normal adult height.


Animal Model

The Drosophila gene 'insulin-like receptor' (InR) is homologous to mammalian insulin receptors. Tatar et al. (2001) described a heteroallelic, hypomorphic genotype of mutant InR, which yields dwarf females with up to an 85% extension of adult longevity and dwarf males with reduced late age-specific mortality. Treatment of the long-lived InR dwarfs with a juvenile hormone analog restores life expectancy toward that of wildtype controls. Tatar et al. (2001) concluded that juvenile hormone deficiency, which results from InR signal pathway mutation, is sufficient to extend life span, and that in flies, insulin-like ligands nonautonomously mediate aging through retardation of growth or activation of specific endocrine tissue.

To define directly the role of Igf1, Kulkarni et al. (2002) created a mouse with a beta cell-specific knockout of Igf1r. Igf1r -/- mice showed normal growth and development of beta cells, but had reduced expression of Glut2 (SLC2A2; 138160), the glucose transporter in islet cells, and of Gck (138079) which encodes glucokinase in beta cells. The result was defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, it was demonstrated that Igf1r is not crucial for islet beta cell development, but participates in control of differentiated function.

Ueki et al. (2006) created mice lacking both Insr and Igf1r only in pancreatic beta cells. These mice were born with the normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. At 2 weeks of age, normoglycemic beta cell-specific double-knockout mice showed reduced beta cell mass, reduced expression of phosphorylated Akt1 (164730) and the transcription factor MafA (610303), increased apoptosis in islets, and severely compromised beta cell function. Analyses of compound knockout showed a dominant role for insulin signaling in regulating beta cell mass. Ueki et al. (2006) concluded that insulin- and IGF1-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes.

Fernandez et al. (2001) developed transgenic mice overexpressing a dominant-negative IGF1R, containing a mutation that abolishes ATPase activity, specifically targeted to skeletal muscle. They found that mutant IGF1R impairs the function of both the normal endogenous IGF1R and the insulin receptor, and that mice overexpressing the mutant IGF1R developed insulin resistance and pancreatic beta-cell dysfunction followed by diabetes. By coimmunoprecipitation experiments, Fernandez et al. (2001) showed interaction between mutant and normal IGF1R hemireceptors as well as between mutant IGF1R and INSR (147670), suggesting the formation of nonfunctional hybrid receptors. Through biochemical analysis, they showed that the mutant hemireceptor fails to autophosphorylate and thereby abrogates the normal function of the hybrid receptors.

To identify genetic determinants of hypoxic cell death, Scott et al. (2002) screened for hypoxia-resistant mutants in C. elegans and found that specific reduction-of-function mutants of daf2, an insulin/insulin-like growth factor receptor homolog gene, were profoundly hypoxia-resistant. The hypoxia resistance was acutely inducible just before hypoxic exposure and was mediated through the AKT1/PDK1/forkhead transcription factor pathway overlapping with but distinct from signaling pathways regulating life span and stress resistance. Selective neuronal and muscle expression of daf2 wildtype restored hypoxic death, and daf2 reduction of function mutants prevented hypoxia-induced muscle and neuronal cell death, demonstrating a potential for insulin/insulin-like growth factor receptor modulation in prophylaxis against hypoxic injury of neurons and myocytes.

Liu et al. (1993) generated mice deficient for Igf1r by targeted disruption. Homozygous mutants died at birth of respiratory failure and exhibited severe growth deficiency (approximately 45% of normal size). In addition to generalized organ hypoplasia in Igf1r -/- embryos, which included the muscles, and developmental delays in ossification, deviations from normal were observed in the central nervous system and epidermis. Holzenberger et al. (2003) studied heterozygous Igf1r knockout mice (Igf1r +/-) and found that they lived an average of 26% longer than their wildtype littermates. Female Igf1r +/- mice lived 33% longer than wildtype females, whereas the equivalent male mice showed an increase in life span of 16%, which was not statistically significant. Long-lived Igf1r +/- mice did not develop dwarfism, their energy metabolism was normal, and their nutrient uptake, physical activity, fertility, and reproduction were unaffected. The Igf1r +/- mice displayed greater resistance to oxidative stress, a known determinant of aging. Holzenberger et al. (2003) concluded that the Igf1 receptor may be a central regulator of mammalian life span.

Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR, IGF1R, and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry (480000) and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination.

Kondo et al. (2003) observed that, following relative hypoxia, mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) showed a 57% decrease in retinal neovascularization compared to controls, which was associated with a blunted rise in the vascular mediators VEGF (192240), eNOS (NOS3; 163729), and endothelin-1 (EDN1; 131240). Mice with a vascular endothelial cell-specific knockout of the Igf1 receptor (VENIFARKO) showed only a 34% reduction in neovascularization and a very modest reduction in mediator generation. Kondo et al. (2003) concluded that both insulin and IGF1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with insulin having a greater effect.

Signal transduction by the insulin receptor pathway has been implicated in life span regulation of multiple vertebrate and invertebrate animal models and is therefore thought to be a widely conserved mechanism in the control of aging among higher eukaryotes. Wessells et al. (2004) addressed the question of the extent to which organ-specific gene effects are involved in life span. Drosophila melanogaster was considered well suited for these studies, not only because of its short life span and genetic versatility, but also because it contains a simple organ with relevance to aging, the heart, which is formed by highly conserved molecular mechanisms and undergoes, as in humans, physiologic changes as it ages. Wessells et al. (2004) described progressive changes in heart function in aging fruit flies: a decrease in resting heart rate and increase in the rate of stress-induced heart failure. These age-related changes were minimized or absent in long-lived flies when systemic levels of insulin-like peptides were reduced and by mutations of the only receptor, the homolog of IGF1R, or its substrate, Chico. Moreover, interfering with insulin-IGF receptor signaling exclusively in the heart, by overexpressing the phosphatase PTEN (601728) or the forkhead transcription factor FOXO (136533), prevented the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on life span.


ALLELIC VARIANTS ( 9 Selected Examples):

.0001 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG108GLN
  
RCV000015913

In 1 of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, Abuzzahab et al. (2003) identified compound heterozygosity for 2 mutations in exon 2 of the IGF1R gene: an arg108-to-gln (R108Q) substitution and a lys115-to-asn (K115N; 147370.0002) substitution. At the age of 4.5 years, her serum IGF1 (147440) concentration was normal, although later it was found to be elevated, suggesting IGF1 resistance (IGF1RES; 270450).


.0002 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, LYS115ASN
  
RCV000015914

For discussion of the lys115-to-asn (K115N) mutation in the IGF1R gene that was found in compound heterozygous state in a patient with resistance to insulin-like growth factor-1 (IGF1RES; 270450) by Abuzzahab et al. (2003), see 147370.0001.


.0003 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG59TER
  
RCV000015915

In 1 boy from a cohort of 50 children with short stature who had elevated circulating IGF1 concentrations (IGF1RES; 270450), Abuzzahab et al. (2003) identified an arg59-to-ter (R59X) mutation in the IGF1R gene, which reduced the number of IGF1 receptors on fibroblasts. The proband's mother and a half sib, who were both small for gestational age at birth, also carried the R59X mutation.

Raile et al. (2006) restudied the 2 half brothers and their mother in whom Abuzzahab et al. (2003) had identified the R59X mutation. In addition to short stature, both boys exhibited primary microcephaly, dysmorphic facial features, and mild mental retardation; their mother also was delayed in school. In vivo and in vitro IGF1 resistance in patient fibroblasts indicated a human IGF1R gene dosage effect involving not only IGF1R, but also IGF1R/insulin receptor (INSR; 147670) hybrids. Raile et al. (2006) concluded that the abundance of both the IGF1R protein and IGF1R/INSR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.


.0004 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG709GLN
  
RCV000015916...

In a 6-year-old Japanese girl and her mother, both of whom were born with intrauterine growth retardation (IUGR) and had short stature (IGF1RES; 270450), Kawashima et al. (2005) found a heterozygous arg709-to-gln (R709Q) mutation in the IGF1R gene that changed the cleavage site from arg-lys-arg-arg to arg-lys-gln-arg. The daughter was also diagnosed with mental retardation. Fibroblasts from the mother contained more IGF1R proreceptor protein and less mature beta-subunit protein, and both IGF1-stimulated [3H]thymidine incorporation and IGF1R beta-subunit autophosphorylation were low compared with those of control (p less than 0.05). The authors concluded that this mutation leads to failure of processing of the IGF1R proreceptor to mature IGF1R, causing IGF1 receptor dysfunction.


.0005 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG481GLN
  
RCV000015917...

In a 13-year-old girl with intrauterine and postnatal growth retardation who also exhibited increased serum IGF I levels (IGF1RES; 270450), Inagaki et al. (2007) identified heterozygosity for a 1577G-A transition in exon 7 of the IGF1R gene, resulting in an arg481-to-gln (R481Q) substitution. The mutation was also present in the girl's maternal aunt, who had short stature (-5 SD); mutation status of the proband's mother was not reported. Functional analysis in transfected NIH-3T3 fibroblasts showed reduced levels of the fold increase of IGF1R beta-subunit phosphorylation as well as ERK1/2 (601795/176948) and AKT (see 164730) phosphorylation, which was accompanied by decreased cell proliferation, with overexpression of the mutant compared to wildtype IGF1R.


.0006 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, GLU121LYS
  
RCV000516173

In a Lebanese brother and sister with intrauterine growth retardation, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Fang et al. (2012) identified compound heterozygosity for missense mutations in the IGF1R gene: a c.361G-A transition in exon 2, resulting in a glu121-to-lys (E121K) substitution, and a c.700G-A transition in exon 3, resulting in a glu234-to-lys (E234K; 147370.0007) substitution. Their unaffected consanguineous parents were each heterozygous for 1 of the mutations. Analysis of patient fibroblasts showed an 80% reduction in processed alpha and beta subunits compared to controls; in contrast, IGF1R precursor and alpha and beta subunits in the fibroblasts of their mother, who was heterozygous for E121K, were indistinguishable from controls. In transfected HEK293 cells, ERK activation was significantly reduced with the E121K mutant compared to wildtype, and ERK activation was comparable to vector with the E234K mutant. Consistent with these findings, patient fibroblasts responded poorly to IGF1 stimulation, showing an 85% reduction in AKT activation compared to control fibroblasts. The brother developed insulin-requiring diabetes mellitus in adolescence (see 222100), whereas the sister died at age 5 years from Burkitt lymphoma (see 113970).


.0007 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, GLU234LYS
  
RCV000516167

For discussion of the c.700G-A transition in exon 3 of the IGF1R gene, resulting in a glu234-to-lys (E234K) substitution, that was found in compound heterozygous state in 2 sibs with resistance to insulin-like growth factor I (IGF1RES; 270450) by Fang et al. (2012), see 147370.0006.


.0008 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG10LEU
  
RCV000516171

In a 13.5-year-old Lebanese girl with intrauterine growth retardation, short stature, microcephaly, dysmorphic facial features, reduced subcutaneous fat, mild developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Gannage-Yared et al. (2013) identified homozygosity for a c.119G-T transversion (c.119G-T, NM_000875) in exon 2 of the IGF1R gene, resulting in an arg10-to-leu (R10L) substitution at a highly conserved residue within the ligand-binding L1 domain. Her unaffected first-cousin parents were both heterozygous for the mutation. Analysis of patient skin fibroblasts showed diminished but not abrogated IGF-binding-related autophosphorylation of IGF1R, and a requirement for higher IGF1 doses to achieve similar levels of AKT phosphorylation compared to control cells.


.0009 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, c.2201G-T, EX10
  
RCV000516174

In a 2-year-old Italian girl with severe intrauterine growth retardation, short stature, microcephaly, progeroid features, developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Prontera et al. (2015) identified homozygosity for a c.2201G-T transversion (c.2201G-T, NM_000875.4) at the last nucleotide of exon 10 in the IGF1R gene. Direct sequencing of amplified products revealed an aberrant isoform generating a mutant protein containing 25 additional amino acids (Pro733_Arg734ins25). Her short-statured consanguineous parents were heterozygous for the mutation, as were both of her grandmothers, who had short stature and type 2 diabetes. Fibroblast cell lines from the patient and her father showed impaired autophosphorylation as well as reduced activation of the IGF1 and insulin-AKT downstream signaling pathways compared to controls, with greater impairment demonstrated with the patient's cells than with those of her father.


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Matthew B. Gross - updated : 02/26/2021
Ada Hamosh - updated : 09/29/2020
Ada Hamosh - updated : 05/08/2019
Marla J. F. O'Neill - updated : 12/12/2017
John A. Phillips, III - updated : 1/14/2009
Marla J. F. O'Neill - updated : 5/29/2008
Patricia A. Hartz - updated : 5/16/2008
John A. Phillips, III - updated : 4/1/2008
Victor A. McKusick - updated : 10/22/2007
John A. Phillips, III - updated : 7/17/2007
Patricia A. Hartz - updated : 11/29/2006
Paul J. Converse - updated : 11/10/2006
John A. Phillips, III - updated : 5/11/2006
Victor A. McKusick - updated : 4/27/2006
John A. Phillips, III - updated : 3/31/2005
Marla J. F. O'Neill - updated : 3/16/2005
Victor A. McKusick - updated : 12/7/2004
John A. Phillips, III - updated : 7/29/2004
Victor A. McKusick - updated : 12/18/2003
Ada Hamosh - updated : 12/1/2003
Jane Kelly - updated : 8/22/2003
Ada Hamosh - updated : 12/10/2002
Ada Hamosh - updated : 7/24/2002
Jane Kelly - updated : 7/9/2002
Patricia A. Hartz - updated : 4/29/2002
Patricia A. Hartz - updated : 4/17/2002
Victor A. McKusick - updated : 4/3/2002
Dawn Watkins-Chow - updated : 6/28/2001
Ada Hamosh - updated : 4/9/2001
John A. Phillips, III - updated : 12/6/2000
Ada Hamosh - updated : 5/31/2000
John A. Phillips, III - updated : 2/9/1999
Creation Date:
Victor A. McKusick : 6/2/1986
mgross : 02/26/2021
alopez : 09/29/2020
alopez : 05/08/2019
carol : 12/14/2017
carol : 12/12/2017
alopez : 03/09/2016
mcolton : 5/4/2015
carol : 4/12/2013
alopez : 6/7/2012
alopez : 4/2/2009
alopez : 3/30/2009
wwang : 3/6/2009
ckniffin : 2/16/2009
alopez : 1/14/2009
wwang : 10/6/2008
carol : 5/29/2008
mgross : 5/16/2008
carol : 4/1/2008
carol : 10/24/2007
terry : 10/22/2007
terry : 10/22/2007
alopez : 7/17/2007
mgross : 11/29/2006
mgross : 11/10/2006
alopez : 11/7/2006
terry : 11/6/2006
mgross : 8/9/2006
alopez : 5/11/2006
wwang : 5/4/2006
wwang : 4/27/2006
terry : 10/12/2005
alopez : 3/31/2005
wwang : 3/17/2005
wwang : 3/16/2005
alopez : 12/9/2004
terry : 12/7/2004
tkritzer : 10/29/2004
alopez : 7/29/2004
ckniffin : 6/25/2004
carol : 6/24/2004
ckniffin : 6/22/2004
mgross : 3/17/2004
tkritzer : 12/19/2003
tkritzer : 12/18/2003
alopez : 12/2/2003
alopez : 12/2/2003
terry : 12/1/2003
mgross : 8/22/2003
alopez : 1/15/2003
alopez : 12/12/2002
terry : 12/10/2002
cwells : 7/24/2002
terry : 7/24/2002
mgross : 7/9/2002
terry : 6/27/2002
alopez : 5/8/2002
carol : 4/30/2002
terry : 4/29/2002
carol : 4/17/2002
carol : 4/17/2002
alopez : 4/3/2002
terry : 4/3/2002
mgross : 6/28/2001
alopez : 4/10/2001
terry : 4/9/2001
mgross : 12/6/2000
mgross : 12/6/2000
alopez : 5/31/2000
mgross : 2/10/1999
mgross : 2/9/1999
dkim : 9/11/1998
terry : 5/29/1998
mark : 7/3/1997
mark : 10/11/1996
mark : 10/7/1996
carol : 10/13/1994
carol : 12/17/1992
supermim : 3/16/1992
carol : 10/11/1991
carol : 8/9/1991
carol : 3/15/1991

* 147370

INSULIN-LIKE GROWTH FACTOR I RECEPTOR; IGF1R


HGNC Approved Gene Symbol: IGF1R

SNOMEDCT: 715625007;   ICD10CM: E34.322;  


Cytogenetic location: 15q26.3     Genomic coordinates (GRCh38): 15:98,648,539-98,964,530 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q26.3 Insulin-like growth factor I, resistance to 270450 Autosomal dominant; Autosomal recessive 3

TEXT

Cloning and Expression

Flier et al. (1986) studied a monoclonal antibody to the receptor for type I insulin-like growth factor (IGF1; 147440).

Ullrich et al. (1986) determined the complete primary structure of the receptor for IGF I from cloned cDNA. The deduced sequence predicts a 1,367-amino acid receptor precursor, including a 30-residue signal peptide, which is removed during translocation of the nascent polypeptide chain. Cleavage of the precursor generates alpha and beta subunits as in the case of the insulin receptor (INSR; 147670).

Using an in vitro self-selection technique, Salehi-Ashtiani et al. (2006) identified a self-cleaving ribozyme associated with the IGF1R gene.


Biochemical Features

Crystal Structure

Lou et al. (2006) reported the crystal structure of the first 3 domains of INSR at 2.3-angstrom resolution and compared it with the structure of the corresponding fragment of IGF1R. They observed notable differences in the regions governing ligand specificity and binding.


Gene Structure

Abbott et al. (1992) determined that the IGF1R gene contains 21 exons and spans about 100 kb. Cooke et al. (1991) analyzed the promoter region and found that the 5-prime flanking and untranslated region is GC-rich and contains numerous potential SP1 and AP2 binding sites as well as a thyroid response element, but no TATA or CCAAT elements.


Mapping

Francke et al. (1986) assigned the IGF1R locus to 15q25-q26 by use of a DNA probe in somatic cell hybrids and for in situ hybridization. Most grains in the latter experiments were in distal q26.

Roback et al. (1991) localized the IGF1R gene distal to chromosome 15q26.1 based on findings from a patient with a 15q26.1-qter deletion and monozygosity for IGF1R.

With a method that combined PCR and single-strand conformation polymorphism (SSCP) analysis for identifying polymorphisms in the 3-prime untranslated regions of genes, Poduslo et al. (1991) identified an insertion/deletion polymorphism of the IGF1R gene and corroborated localization to chromosome 15q25-q26.

Gross (2021) mapped the IGF1R gene to chromosome 15q26.3 based on an alignment of the IGF1R sequence (GenBank BC113610) with the genomic sequence (GRCh38).


Gene Function

Prager et al. (1992) showed that a mutant human IGF-I receptor interfered with the expected suppression of growth hormone in cultured rat pituitary cells, thus demonstrating a dominant-negative phenotype. (The 'dominant-negative' concept was first clearly articulated by Herskowitz (1987). He recognized 2 classes. The first class comprises multimeric proteins dependent on oligomerization for activity; the presence in a multimer of a mutant subunit with intact binding but altered catalytic domains can abrogate the function of the entire multimer. The second class involves monomeric proteins, in which dominant-negative mutations can occur if substrate is limiting; a mutant able to bind the substrate but not metabolize it would have this effect.)

Using a yeast 2-hybrid system, Dey et al. (1998) identified a regulatory subunit of phosphatidylinositol (PI) 3-kinase, PIK3R3 (606076), as a binding partner of IGF1R. They concluded that the SH2 domain of PIK3R3 interacts with IGF1R and INSR in a kinase-dependent manner, providing an alternative pathway for the activation of PI 3-kinase by these 2 receptors.

Rotem-Yehudar et al. (2001) found evidence that IGF1R associated with SNAP29 (604202), a synaptosomal-associated protein, and with EHD1 (605888), a protein containing motifs important for protein-protein interaction and for intracellular sorting. Through immunoprecipitation of rat tissues, they found that SNAP29 and EHD1 are present in complexes with IGF1R. They also found that IGF1 induction of EHD1-transfected CHO cells results in intracellular colocalization of EHD1 and IGF1R.

In 15 informative patients with embryonal tumors (Wilms tumor, hepatoblastoma, and adrenal tumors), Howard et al. (1993) examined IGF1R gene expression for evidence of imprinting. All but one sample of normal juvenile kidney and liver and associated tumors showed biallelic expression, suggesting that the human gene is not normally imprinted as it is in the mouse, where both Igf1r and Igf2r are imprinted. The exception in the study of Howard et al. (1993) was a patient with Beckwith-Wiedemann syndrome (130650) in which monoallelic expression of the maternally derived IGF1R allele was found in normal kidney, associated Wilms tumor, and peripheral blood lymphocytes. By demonstrating biallelic expression, Ogawa et al. (1993) likewise showed that both the IGF1R and IGF2R (147280) genes are expressed equally from the maternal and paternal alleles in human tissues.

The insulin-like growth factor I receptor plays a critical role in transformation events. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. The p53 gene (191170), the most frequently mutated gene in human cancer, is a nuclear transcription factor that blocks cell cycle progression and induces apoptosis. Werner et al. (1996) reported results of experiments that indicated that mutant p53 proteins have a stimulatory effect on promoter activity, whereas wildtype p53 suppresses the activity of the IGF1R promoter. These effects of p53 seemed to involve its interaction with components of the basal transcription machinery. Due to the central role of IGF1R in cell cycle progression and transformation, derepression of IGF1R promoter by mutant p53 may constitute an important paradigm in tumorigenesis. (Most of the cancer-related mutations of p53 occur in the central domain of the p53 molecule.)

Maor et al. (2000) cotransfected a luciferase reporter gene under the control of the IGF1R promoter with a wildtype BRCA1 (113705)-encoding expression vector into multiple cell lines. They observed a significant reduction in luciferase activity in all 3 cell lines tested, demonstrating suppression of promoter activity by BRCA1 in a dose-dependent manner. Functional interaction between BRCA1 and SP1 (189906) in the regulation of the IGF1R gene was studied in Schneider cells, a Drosophila cell line which lacks endogenous SP1. In these cells, BRCA1 suppressed 45% of the SP1-induced trans-activation of the IGF1R promoter. Maor et al. (2000) concluded that BRCA1 is capable of suppressing the IGF1R promoter in a number of cell lines, resulting in low levels of receptor mRNA protein. Maor et al. (2000) hypothesized that mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF1R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may elicit a myogenic event which may be a key mechanism in the etiology of breast and ovarian cancer.

Stromal cells derived from benign prostatic hyperplasia (600082) synthesize and secrete measurable levels of insulin-like growth factors I and II (IGF2; 147470). Grant et al. (1998) used RT-PCR analysis to demonstrate that the genes for both the type I receptor and the type II receptor are expressed by benign stromal cells in vitro. Incubation with the IGF1R-neutralizing antibody alpha-IR3 (50 microg/mL) reduced the rate of stromal cell proliferation by approximately 60 to 80%, even in the presence of stimulatory concentrations of IGF. Camptothecin-induced apoptosis was inhibited by the addition of IGF1 and IGF2 (500 ng/mL). The authors concluded that IGF1R is a pivotal molecule in prostatic stromal cell maintenance and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.

All-Ericsson et al. (2002) investigated the expression of IGF1R, focusing on its role in cell growth in uveal melanoma (155720). Their data suggested a significant association between high IGF1R expression and death due to metastatic disease. Because IGF1R is produced mainly in the liver, the preferential site for uveal melanoma metastases, these results pointed to the possibility of interfering therapeutically with IGF1R in uveal melanoma that appears to follow an aggressive clinical course.

Lambooij et al. (2003) demonstrated that IGF1 and IGF1R were present in capillary endothelial cells, retinal pigment epithelial cells, and fibroblast-like cells in choroidal neovascular membranes of age-related macular degeneration (see 153800).

Self-renewal and multi-lineage developmental potential define the unique properties of stem cells. In vivo, these properties are not autonomously achieved, and evidence points to a level of external control from the microenvironment. Bendall et al. (2007) demonstrated that these 2 properties depend on a dynamic interplay between human embryonic stem (ES) cells and autologously derived human ES cell fibroblast-like cells (hdFs). Both ES cells and hdFs are defined by dependence on insulin-like growth factor (IGF) and fibroblast growth factor (FGF). IGF1R expression was exclusive to the human ES cells, whereas FGFR1 (136350) expression was restricted to the surrounding hdFs. Blocking the IGF-II/IGF1R pathway reduced survival and clonogenicity of human ES cells, whereas inhibition of the FGF pathway indirectly caused differentiation. IGF-II is expressed by hdFs in response to FGF, and alone was sufficient in maintaining ES cell cultures. This study demonstrated a direct role of the IGF-II/IGF1R axis on human ES cell physiology and established that hdFs produced by human ES cells themselves define the stem cell niche of pluripotent human stem cells.

Giovannone et al. (2003) found that a fragment of mouse Gigyf1 (612064) containing the GYF domain bound Grb10 (601523) in mouse fibroblasts expressing Igf1r in the basal state. Stimulation with Igf1 resulted in increased binding of Gigyf1 to Grb10 and transient binding of Gigyf1 and Grb10 to Igf1r, presumably via the adaptor function of Grb10. At later time points, Gigyf1 dissociated, but Grb10 remained linked to Igf1r. Overexpression of the Grb10-binding fragment of Gigyf1 resulted in a significant increase in Igf1-stimulated Igf1r tyrosine phosphorylation. Giovannone et al. (2003) concluded that GRB10 and GIGYF1 may act cooperatively to regulate IGF1R signaling.

Using PCR, Sun et al. (2014) identified IRAIN (619212), a long noncoding RNA (lncRNA) transcribed from the IGF1R gene locus in human leukemia cells. Further analysis showed that IRAIN transcription occurs antisense to IGF1R, originates from a promoter in IGF1R intron 1, and overlaps the promoter and exon 1 of IGF1R. Allelic expression analysis indicated that IRAIN is imprinted, with the paternal allele expressed and the maternal allele suppressed. IRAIN bound chromatin DNA in the IGF1R promoter region and in an intronic enhancer in leukemia KG-1 cells. Binding of IRAIN to these regions formed an intrachromosomal loop that likely allowed IRAIN to be actively involved in interaction of 2 remote regions of the IGF1R gene.

To gain insight into the biologic pathways associated with nuclear IGF1R action, Solomon-Zemler et al. (2019) conducted a mass spectrometry-based proteomic analysis that identified interactors of IGF1R in nucleus of both benign and malignant breast cells. Using a combination of coimmunoprecipitation and silencing assays, Solomon-Zemler et al. (2019) provided evidence of a complex, bidirectional interplay between nuclear IGF1R and the nucleolar protein NOM1 (611269), which functions in translation, cell growth, and proliferation. Inhibition of nuclear IGF1R translocation by dansylcadaverine, an inhibitor of clathrin-mediated endocytosis into the nucleus, reduced NOM1 levels in nuclei of MCF7 cells. On the other hand, IGF1R overexpression enhanced NOM1 levels in the nuclear fraction. NOM1 silencing led to a major increase in IGF1R biosynthesis. Solomon-Zemler et al. (2019) concluded that their results were consistent with a physiologically relevant interplay between the nuclear IGF1 signaling pathway and nucleolar protein NOM1.

Griffiths et al. (2020) showed a mechanism of RSV entry into cells in which outside-in signaling, involving binding of the prefusion RSV-F glycoprotein with IGF1R, triggers the activation of protein kinase C-zeta (PKC-zeta) (PRKCZ; 176982). This cellular signaling cascade recruits nucleolin (NCL; 164035) from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. Griffiths et al. (2020) found that inhibiting PKC-zeta activation prevented the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduced viral replication and pathology in RSV-infected mice.


Molecular Genetics

Involvement in Growth and Insulin-Related Phenotypes

Approximately 10% of infants with intrauterine growth retardation (IUGR) remain small. Abuzzahab et al. (2003) postulated that mutations in the IGF1R gene resulting in IGF1 resistance (IGF1RES; 270450) might underlie some cases of prenatal and postnatal growth failure. In a group of 42 patients with unexplained IUGR and subsequent short stature, they found a girl who was compound heterozygous for missense mutations in IGF1R (R108Q, 147370.0001 and K115N, 147370.0002). Fibroblasts cultured from the patient had decreased IGF1 receptor function, as compared with that in control fibroblasts. In a cohort of 50 children with short stature who had elevated circulating IGF1 concentrations, Abuzzahab et al. (2003) identified 1 boy with a heterozygous nonsense mutation (R59X; 147370.0003) in IGF1R that reduced the number of IGF1 receptors on fibroblasts. Both children had IUGR, poor postnatal growth, and mild developmental delay; the boy also exhibited dysmorphic features.

Kawashima et al. (2005) screened 24 Japanese patients with unexplained IUGR and short stature for mutations in the IGF1R gene and identified a girl who was heterozygous for a missense mutation (R709Q; 147370.0004). The mutation, which is located within the cleavage site and results in failure of processing of the precursor protein to mature IGF1R, was also present in the proband's affected mother.

In a 13.6-year-old Russian girl with IUGR and short stature and in her aunt who had short stature, Inagaki et al. (2007) identified heterozygosity for a missense mutation in the IGF1R gene (R481Q; 147370.0005).

In a Lebanese brother and sister with IUGR, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels, Fang et al. (2012) sequenced the IGF1 and IGF1R genes and identified compound heterozygosity for missense mutations in the IGF1R gene (E121K, 147370.0006 and E234K, 147370.0007). Their unaffected consanguineous parents were each heterozygous for 1 of the mutations.

In a 13.5-year-old girl, born of first-cousin Lebanese parents, who had severe IUGR, short stature, microcephaly, facial dysmorphism, reduced subcutaneous fat, mild developmental delay, and elevated IGF1 levels, Gannage-Yared et al. (2013) sequenced the IGF1 and IGF1R genes and identified homozygosity for a missense mutation in the IGF1R gene (R10L; 147370.0008), for which her unaffected parents were heterozygous.

In a 2-year-old Italian girl with severe IUGR, short stature, microcephaly, progeroid features, developmental delay, and elevated IGF1 levels, Prontera et al. (2015) identified homozygosity for a c.2201G-T transversion in the IGF1R gene (147370.0009), predicted to affect the splicing process. Her short-statured consanguineous parents were heterozygous for the mutation, as were both of her grandmothers, who had short stature and type 2 diabetes (125853).

Involvement in Longevity

Downregulation of the IGF1 pathway or IGF1 plasma levels has been associated with an increased life span (see 152430). Bonafe et al. (2003) tested the hypothesis that polymorphic variants of IGF1 response pathway genes, namely IGF1R (G/A, codon 1013), PIK3CB (602925) (T/C, -359 bp; A/G, -303 bp), IRS1 (147545) (G/A, codon 972), and FOXO1A (136533) (T/C, +97347 bp), play a role in systemic IGF1 regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF1R had low levels of free plasma IGF1 and were more represented among long-lived people. Moreover, genotype combinations at IGF1R and PIK3CB genes affect free IGF1 plasma levels and longevity. Genotype combinations of an A allele at the IGF1R locus and a T allele at the PIK3CB locus (A+/T+ subjects) affect IGF1 plasma levels (having A-/T- individuals the highest free IGF1 plasma levels), as well as longevity, and the proportion of A+/T+ subjects significantly increased among long-lived individuals.

Suh et al. (2008) studied biochemical, phenotypic, and genetic variation in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGF1 associated with smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1R genes showed overrepresentation of heterozygous mutations in the IGF1R gene among female centenarians relative to controls that were associated with high serum IGF1 levels and reduced activity of IGF1R as measured in transformed lymphocytes. Suh et al. (2008) concluded that genetic variations in IGF1R that alter the IGF signaling pathway may play a role in modulation of human life span.

Exclusion Studies

Rasmussen et al. (2000) considered the IGF1 and IGF1R genes as candidates for low birth weight, insulin resistance, and type 2 diabetes. In genomic DNA from probands of 82 Danish families with type II diabetes, they identified no mutations predicting changes in the amino acid sequences of the IGF1 or IGF1R genes, although several silent and intronic polymorphisms were identified. The authors concluded that variability in the coding regions of IGF1 and IGF1R does not associate with reduced birth weight, insulin sensitivity index, or type II diabetes in the Danish population.


Cytogenetics

Roback et al. (1991) described a patient with a chromosome 15q26.1-qter deletion (612626) and monozygosity for the IGF1R gene. Clinical features of the patient included intrauterine growth retardation (IUGR), microcephaly, micrognathia, renal anomalies, lung hypoplasia, and delayed growth and development. The authors reviewed the clinical findings in patients with similar chromosome 15 deletions and speculated that the loss of an IGF1R allele may be related to the severe IUGR and postnatal growth deficiency observed in their patient and other patients with distal 15q deletions.

Okubo et al. (2003) reported 2 children with altered numbers of IGF1R alleles who presented with abnormal growth. Case 1 was a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal, but karyotype analysis identified a deletion on 15q26.2, and a FISH study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and had rapid, early postnatal growth. He had a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A FISH study using the same probes showed 3 copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only 1 IGF1R allele showed slower growth, whereas cells from the subject with 3 IGF1R alleles showed accelerated growth compared with controls.

Walenkamp et al. (2008) reported a 15-year-old girl with heterozygous deletion of 15q26.2-qter, including the IGF1R gene, who had been small for gestational age and who showed persistent postnatal growth retardation, microcephaly, and elevated IGF1 levels. She had been treated with growth hormone since the age of 5 years, which resulted in a good growth response and normal adult height.


Animal Model

The Drosophila gene 'insulin-like receptor' (InR) is homologous to mammalian insulin receptors. Tatar et al. (2001) described a heteroallelic, hypomorphic genotype of mutant InR, which yields dwarf females with up to an 85% extension of adult longevity and dwarf males with reduced late age-specific mortality. Treatment of the long-lived InR dwarfs with a juvenile hormone analog restores life expectancy toward that of wildtype controls. Tatar et al. (2001) concluded that juvenile hormone deficiency, which results from InR signal pathway mutation, is sufficient to extend life span, and that in flies, insulin-like ligands nonautonomously mediate aging through retardation of growth or activation of specific endocrine tissue.

To define directly the role of Igf1, Kulkarni et al. (2002) created a mouse with a beta cell-specific knockout of Igf1r. Igf1r -/- mice showed normal growth and development of beta cells, but had reduced expression of Glut2 (SLC2A2; 138160), the glucose transporter in islet cells, and of Gck (138079) which encodes glucokinase in beta cells. The result was defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, it was demonstrated that Igf1r is not crucial for islet beta cell development, but participates in control of differentiated function.

Ueki et al. (2006) created mice lacking both Insr and Igf1r only in pancreatic beta cells. These mice were born with the normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. At 2 weeks of age, normoglycemic beta cell-specific double-knockout mice showed reduced beta cell mass, reduced expression of phosphorylated Akt1 (164730) and the transcription factor MafA (610303), increased apoptosis in islets, and severely compromised beta cell function. Analyses of compound knockout showed a dominant role for insulin signaling in regulating beta cell mass. Ueki et al. (2006) concluded that insulin- and IGF1-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes.

Fernandez et al. (2001) developed transgenic mice overexpressing a dominant-negative IGF1R, containing a mutation that abolishes ATPase activity, specifically targeted to skeletal muscle. They found that mutant IGF1R impairs the function of both the normal endogenous IGF1R and the insulin receptor, and that mice overexpressing the mutant IGF1R developed insulin resistance and pancreatic beta-cell dysfunction followed by diabetes. By coimmunoprecipitation experiments, Fernandez et al. (2001) showed interaction between mutant and normal IGF1R hemireceptors as well as between mutant IGF1R and INSR (147670), suggesting the formation of nonfunctional hybrid receptors. Through biochemical analysis, they showed that the mutant hemireceptor fails to autophosphorylate and thereby abrogates the normal function of the hybrid receptors.

To identify genetic determinants of hypoxic cell death, Scott et al. (2002) screened for hypoxia-resistant mutants in C. elegans and found that specific reduction-of-function mutants of daf2, an insulin/insulin-like growth factor receptor homolog gene, were profoundly hypoxia-resistant. The hypoxia resistance was acutely inducible just before hypoxic exposure and was mediated through the AKT1/PDK1/forkhead transcription factor pathway overlapping with but distinct from signaling pathways regulating life span and stress resistance. Selective neuronal and muscle expression of daf2 wildtype restored hypoxic death, and daf2 reduction of function mutants prevented hypoxia-induced muscle and neuronal cell death, demonstrating a potential for insulin/insulin-like growth factor receptor modulation in prophylaxis against hypoxic injury of neurons and myocytes.

Liu et al. (1993) generated mice deficient for Igf1r by targeted disruption. Homozygous mutants died at birth of respiratory failure and exhibited severe growth deficiency (approximately 45% of normal size). In addition to generalized organ hypoplasia in Igf1r -/- embryos, which included the muscles, and developmental delays in ossification, deviations from normal were observed in the central nervous system and epidermis. Holzenberger et al. (2003) studied heterozygous Igf1r knockout mice (Igf1r +/-) and found that they lived an average of 26% longer than their wildtype littermates. Female Igf1r +/- mice lived 33% longer than wildtype females, whereas the equivalent male mice showed an increase in life span of 16%, which was not statistically significant. Long-lived Igf1r +/- mice did not develop dwarfism, their energy metabolism was normal, and their nutrient uptake, physical activity, fertility, and reproduction were unaffected. The Igf1r +/- mice displayed greater resistance to oxidative stress, a known determinant of aging. Holzenberger et al. (2003) concluded that the Igf1 receptor may be a central regulator of mammalian life span.

Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR, IGF1R, and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry (480000) and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination.

Kondo et al. (2003) observed that, following relative hypoxia, mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) showed a 57% decrease in retinal neovascularization compared to controls, which was associated with a blunted rise in the vascular mediators VEGF (192240), eNOS (NOS3; 163729), and endothelin-1 (EDN1; 131240). Mice with a vascular endothelial cell-specific knockout of the Igf1 receptor (VENIFARKO) showed only a 34% reduction in neovascularization and a very modest reduction in mediator generation. Kondo et al. (2003) concluded that both insulin and IGF1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with insulin having a greater effect.

Signal transduction by the insulin receptor pathway has been implicated in life span regulation of multiple vertebrate and invertebrate animal models and is therefore thought to be a widely conserved mechanism in the control of aging among higher eukaryotes. Wessells et al. (2004) addressed the question of the extent to which organ-specific gene effects are involved in life span. Drosophila melanogaster was considered well suited for these studies, not only because of its short life span and genetic versatility, but also because it contains a simple organ with relevance to aging, the heart, which is formed by highly conserved molecular mechanisms and undergoes, as in humans, physiologic changes as it ages. Wessells et al. (2004) described progressive changes in heart function in aging fruit flies: a decrease in resting heart rate and increase in the rate of stress-induced heart failure. These age-related changes were minimized or absent in long-lived flies when systemic levels of insulin-like peptides were reduced and by mutations of the only receptor, the homolog of IGF1R, or its substrate, Chico. Moreover, interfering with insulin-IGF receptor signaling exclusively in the heart, by overexpressing the phosphatase PTEN (601728) or the forkhead transcription factor FOXO (136533), prevented the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on life span.


ALLELIC VARIANTS 9 Selected Examples):

.0001   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG108GLN
SNP: rs121912426, gnomAD: rs121912426, ClinVar: RCV000015913

In 1 of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, Abuzzahab et al. (2003) identified compound heterozygosity for 2 mutations in exon 2 of the IGF1R gene: an arg108-to-gln (R108Q) substitution and a lys115-to-asn (K115N; 147370.0002) substitution. At the age of 4.5 years, her serum IGF1 (147440) concentration was normal, although later it was found to be elevated, suggesting IGF1 resistance (IGF1RES; 270450).


.0002   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, LYS115ASN
SNP: rs121912427, gnomAD: rs121912427, ClinVar: RCV000015914

For discussion of the lys115-to-asn (K115N) mutation in the IGF1R gene that was found in compound heterozygous state in a patient with resistance to insulin-like growth factor-1 (IGF1RES; 270450) by Abuzzahab et al. (2003), see 147370.0001.


.0003   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG59TER
SNP: rs121912428, ClinVar: RCV000015915

In 1 boy from a cohort of 50 children with short stature who had elevated circulating IGF1 concentrations (IGF1RES; 270450), Abuzzahab et al. (2003) identified an arg59-to-ter (R59X) mutation in the IGF1R gene, which reduced the number of IGF1 receptors on fibroblasts. The proband's mother and a half sib, who were both small for gestational age at birth, also carried the R59X mutation.

Raile et al. (2006) restudied the 2 half brothers and their mother in whom Abuzzahab et al. (2003) had identified the R59X mutation. In addition to short stature, both boys exhibited primary microcephaly, dysmorphic facial features, and mild mental retardation; their mother also was delayed in school. In vivo and in vitro IGF1 resistance in patient fibroblasts indicated a human IGF1R gene dosage effect involving not only IGF1R, but also IGF1R/insulin receptor (INSR; 147670) hybrids. Raile et al. (2006) concluded that the abundance of both the IGF1R protein and IGF1R/INSR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.


.0004   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG709GLN
SNP: rs121912429, gnomAD: rs121912429, ClinVar: RCV000015916, RCV003886361

In a 6-year-old Japanese girl and her mother, both of whom were born with intrauterine growth retardation (IUGR) and had short stature (IGF1RES; 270450), Kawashima et al. (2005) found a heterozygous arg709-to-gln (R709Q) mutation in the IGF1R gene that changed the cleavage site from arg-lys-arg-arg to arg-lys-gln-arg. The daughter was also diagnosed with mental retardation. Fibroblasts from the mother contained more IGF1R proreceptor protein and less mature beta-subunit protein, and both IGF1-stimulated [3H]thymidine incorporation and IGF1R beta-subunit autophosphorylation were low compared with those of control (p less than 0.05). The authors concluded that this mutation leads to failure of processing of the IGF1R proreceptor to mature IGF1R, causing IGF1 receptor dysfunction.


.0005   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG481GLN
SNP: rs33958176, gnomAD: rs33958176, ClinVar: RCV000015917, RCV000487894, RCV001818163

In a 13-year-old girl with intrauterine and postnatal growth retardation who also exhibited increased serum IGF I levels (IGF1RES; 270450), Inagaki et al. (2007) identified heterozygosity for a 1577G-A transition in exon 7 of the IGF1R gene, resulting in an arg481-to-gln (R481Q) substitution. The mutation was also present in the girl's maternal aunt, who had short stature (-5 SD); mutation status of the proband's mother was not reported. Functional analysis in transfected NIH-3T3 fibroblasts showed reduced levels of the fold increase of IGF1R beta-subunit phosphorylation as well as ERK1/2 (601795/176948) and AKT (see 164730) phosphorylation, which was accompanied by decreased cell proliferation, with overexpression of the mutant compared to wildtype IGF1R.


.0006   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, GLU121LYS
SNP: rs1555434208, ClinVar: RCV000516173

In a Lebanese brother and sister with intrauterine growth retardation, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Fang et al. (2012) identified compound heterozygosity for missense mutations in the IGF1R gene: a c.361G-A transition in exon 2, resulting in a glu121-to-lys (E121K) substitution, and a c.700G-A transition in exon 3, resulting in a glu234-to-lys (E234K; 147370.0007) substitution. Their unaffected consanguineous parents were each heterozygous for 1 of the mutations. Analysis of patient fibroblasts showed an 80% reduction in processed alpha and beta subunits compared to controls; in contrast, IGF1R precursor and alpha and beta subunits in the fibroblasts of their mother, who was heterozygous for E121K, were indistinguishable from controls. In transfected HEK293 cells, ERK activation was significantly reduced with the E121K mutant compared to wildtype, and ERK activation was comparable to vector with the E234K mutant. Consistent with these findings, patient fibroblasts responded poorly to IGF1 stimulation, showing an 85% reduction in AKT activation compared to control fibroblasts. The brother developed insulin-requiring diabetes mellitus in adolescence (see 222100), whereas the sister died at age 5 years from Burkitt lymphoma (see 113970).


.0007   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, GLU234LYS
SNP: rs1253103806, gnomAD: rs1253103806, ClinVar: RCV000516167

For discussion of the c.700G-A transition in exon 3 of the IGF1R gene, resulting in a glu234-to-lys (E234K) substitution, that was found in compound heterozygous state in 2 sibs with resistance to insulin-like growth factor I (IGF1RES; 270450) by Fang et al. (2012), see 147370.0006.


.0008   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, ARG10LEU
SNP: rs1409058783, ClinVar: RCV000516171

In a 13.5-year-old Lebanese girl with intrauterine growth retardation, short stature, microcephaly, dysmorphic facial features, reduced subcutaneous fat, mild developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Gannage-Yared et al. (2013) identified homozygosity for a c.119G-T transversion (c.119G-T, NM_000875) in exon 2 of the IGF1R gene, resulting in an arg10-to-leu (R10L) substitution at a highly conserved residue within the ligand-binding L1 domain. Her unaffected first-cousin parents were both heterozygous for the mutation. Analysis of patient skin fibroblasts showed diminished but not abrogated IGF-binding-related autophosphorylation of IGF1R, and a requirement for higher IGF1 doses to achieve similar levels of AKT phosphorylation compared to control cells.


.0009   INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO

IGF1R, c.2201G-T, EX10
SNP: rs1555460945, ClinVar: RCV000516174

In a 2-year-old Italian girl with severe intrauterine growth retardation, short stature, microcephaly, progeroid features, developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Prontera et al. (2015) identified homozygosity for a c.2201G-T transversion (c.2201G-T, NM_000875.4) at the last nucleotide of exon 10 in the IGF1R gene. Direct sequencing of amplified products revealed an aberrant isoform generating a mutant protein containing 25 additional amino acids (Pro733_Arg734ins25). Her short-statured consanguineous parents were heterozygous for the mutation, as were both of her grandmothers, who had short stature and type 2 diabetes. Fibroblast cell lines from the patient and her father showed impaired autophosphorylation as well as reduced activation of the IGF1 and insulin-AKT downstream signaling pathways compared to controls, with greater impairment demonstrated with the patient's cells than with those of her father.


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Contributors:
Matthew B. Gross - updated : 02/26/2021
Ada Hamosh - updated : 09/29/2020
Ada Hamosh - updated : 05/08/2019
Marla J. F. O'Neill - updated : 12/12/2017
John A. Phillips, III - updated : 1/14/2009
Marla J. F. O'Neill - updated : 5/29/2008
Patricia A. Hartz - updated : 5/16/2008
John A. Phillips, III - updated : 4/1/2008
Victor A. McKusick - updated : 10/22/2007
John A. Phillips, III - updated : 7/17/2007
Patricia A. Hartz - updated : 11/29/2006
Paul J. Converse - updated : 11/10/2006
John A. Phillips, III - updated : 5/11/2006
Victor A. McKusick - updated : 4/27/2006
John A. Phillips, III - updated : 3/31/2005
Marla J. F. O'Neill - updated : 3/16/2005
Victor A. McKusick - updated : 12/7/2004
John A. Phillips, III - updated : 7/29/2004
Victor A. McKusick - updated : 12/18/2003
Ada Hamosh - updated : 12/1/2003
Jane Kelly - updated : 8/22/2003
Ada Hamosh - updated : 12/10/2002
Ada Hamosh - updated : 7/24/2002
Jane Kelly - updated : 7/9/2002
Patricia A. Hartz - updated : 4/29/2002
Patricia A. Hartz - updated : 4/17/2002
Victor A. McKusick - updated : 4/3/2002
Dawn Watkins-Chow - updated : 6/28/2001
Ada Hamosh - updated : 4/9/2001
John A. Phillips, III - updated : 12/6/2000
Ada Hamosh - updated : 5/31/2000
John A. Phillips, III - updated : 2/9/1999

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
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alopez : 09/29/2020
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carol : 12/14/2017
carol : 12/12/2017
alopez : 03/09/2016
mcolton : 5/4/2015
carol : 4/12/2013
alopez : 6/7/2012
alopez : 4/2/2009
alopez : 3/30/2009
wwang : 3/6/2009
ckniffin : 2/16/2009
alopez : 1/14/2009
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carol : 5/29/2008
mgross : 5/16/2008
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alopez : 7/29/2004
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carol : 6/24/2004
ckniffin : 6/22/2004
mgross : 3/17/2004
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alopez : 12/2/2003
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alopez : 4/3/2002
terry : 4/3/2002
mgross : 6/28/2001
alopez : 4/10/2001
terry : 4/9/2001
mgross : 12/6/2000
mgross : 12/6/2000
alopez : 5/31/2000
mgross : 2/10/1999
mgross : 2/9/1999
dkim : 9/11/1998
terry : 5/29/1998
mark : 7/3/1997
mark : 10/11/1996
mark : 10/7/1996
carol : 10/13/1994
carol : 12/17/1992
supermim : 3/16/1992
carol : 10/11/1991
carol : 8/9/1991
carol : 3/15/1991