Alternative titles; symbols
HGNC Approved Gene Symbol: IGF1
SNOMEDCT: 724385009;
Cytogenetic location: 12q23.2 Genomic coordinates (GRCh38): 12:102,395,874-102,481,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.2 | Insulin-like growth factor I deficiency | 608747 | Autosomal recessive | 3 |
The somatomedins, or insulin-like growth factors (IGFs), comprise a family of peptides that play important roles in mammalian growth and development. IGF1 mediates many of the growth-promoting effects of growth hormone (GH; 139250).
Early studies showed that growth hormone did not directly stimulate the incorporation of sulfate into cartilage, but rather acted through a serum factor, termed 'sulfation factor,' which later became known as 'somatomedin' (Daughaday et al., 1972). Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2; 147470), and somatomedin B (193190) (Rotwein, 1986; Rosenfeld, 2003).
Rinderknecht and Humbel (1978) determined that human IGF1 is a single chain 70-amino acid polypeptide cross-linked by 3 disulfide bridges, with a calculated molecular mass of 7.6 kD. The IGF1 protein displays homology to proinsulin (176730). By the solid-phase method, Li et al. (1983) synthesized human somatomedin C and also determined that it has 70 amino acid residues and 3 disulfide bridges.
Jansen et al. (1983) reported the nucleotide sequence of a human liver cDNA encoding the complete amino acid sequence of IGF1. The IGF1 coding region is flanked by sequences encoding an amino-terminal peptide of at least 25 residues and a carboxyl-terminal peptide of 35 amino acids. The findings provided evidence that IGF1 is synthesized as a precursor protein that undergoes proteolytic processing at both ends (see also Ullrich et al., 1984 and Le Bouc et al., 1986).
Using a synthetic oligonucleotide probe to screen a human liver cDNA library, Rotwein (1986) isolated 2 IGF1 cDNA clones encoding protein precursors of 153 and 195 amino acids termed IGF1A and IGF1B, respectively. The authors concluded that the 2 IGF1 mRNAs result from alternative processing of a single gene product and encode 2 different protein precursors, yielding a second level of regulation and processing. They detected a major mRNA of 1.1 kb, but other mRNAs of 1.7, 3.7, and 6.3 kb were also detected.
Kim et al. (1991) identified and characterized a promoter regulatory region of the IGF1 gene.
Sussenbach et al. (1992) noted that the IGF1 and IGF2 genes have complex structures with multiple promoters. The expression of both genes is regulated at the levels of transcription, RNA processing, and translation.
Rotwein et al. (1986) reported that the IGF1 gene contains 5 exons. Exons 1-4 encode the 195-amino acid precursor (IGF1B), and exons 1, 2, 3, and 5 encode the 153-residue peptide (IGF1A). The structure of IGF1 resembles that of IGF2. Smith et al. (2002) reported that the IGF1 gene has 6 exons, 4 of which are alternatively spliced depending on tissue type and hormonal environment.
By somatic cell hybrid analysis, Brissenden et al. (1984) and Tricoli et al. (1984) independently assigned the IGF1 structural gene to chromosome 12. Tricoli et al. (1984) regionalized the locus tentatively to 12q22-qter, where the KRAS2 (190070) gene is situated. This proximity, as well as that of the HRAS1 (190020) and IGF2 (147470) genes on 11p and that of the NRAS (164790) and NGFB (162030) genes in band 1p22, suggested to Brissenden et al. (1984) that a functional or evolutionary relationship may exist between members of the RAS family of protooncogenes and growth factor genes.
By in situ hybridization, Morton et al. (1985, 1986) and Yang-Feng et al. (1985) assigned the IGF1 gene to 12q22-q24.1. Hoppener et al. (1985) commented on the chromosomal proximity of members of the insulin gene family to members of the RAS oncogene family: NGFB and NRAS on 1p; INS (176730), IGF2 and HRAS on 11p; and IGF1 and KRAS on 12. By linkage analysis Bowcock and Sartorelli (1990) demonstrated tight linkage of IGF1 to PAH (612349) on 12q22-q24.1.
Justice et al. (1990) placed the mouse IGF1 gene on chromosome 10. Taylor and Grieco (1991) showed that the mouse IGF1 gene is located in the central part of chromosome 10, a considerable distance from the pygmy mutation (pg) (see 265850).
In the circulation, the IGFs are predominantly bound to binding proteins (IGFBPs) (see, e.g., 146730), which prolong the half-life of the IGFs and play a role in delivering them to target tissues (Yakar et al., 1999). From human serum, Rapp et al. (1988) reported isolation of a single class of high molecular mass binding protein that binds in a comparable manner to both IGF1 and IGF2.
Using a modified yeast 2-hybrid system, Zhu and Kahn (1997) determined that the interaction of IGF1 with its receptor IGF1R (147370) was specific. Proinsulin showed no significant interaction with IGF1R.
Woods et al. (1996) noted that although there is no direct evidence that IGF1 has a prominent role in human fetal growth, fetal tissues express IGF1 from an early stage and fetal and cord serum IGF1 concentrations are correlated with fetal size. IGF1 knockout mice also have defects in neurologic development, indicating that IGF1 may have specific roles in axonal growth and myelination. In addition, neonatal mortality is substantial, suggesting that the defect may be lethal in humans also.
Bianda et al. (1998) studied the effects of IGF1 and GH (139250) on markers of bone turnover in 8 adults with pituitary tumor-related GH deficiency treated with IGF1 and GH in a randomized crossover trial. Serum osteocalcin and C- and N-terminal propeptides of type I procollagen increased significantly within 2 to 3 days of either treatment and returned to baseline levels within 1 week after treatment ended. The changes in resorption markers were less marked as compared with formation markers. Bianda et al. (1998) concluded that since the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF1 is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because parathyroid hormone (PTH), calcium, and phosphate remained unchanged, the authors stated that IGF1 appears to stimulate renal 1-alpha-hydroxylase activity in vivo.
By specific Igf1 gene inactivation in mouse liver, Sjogren et al. (1999) and Yakar et al. (1999) observed a 75% reduction in serum IGF1, confirming that the liver is the major source of IGF1 in the blood. Surprisingly, the mice showed normal postnatal body growth, suggesting that an autocrine or paracrine IGF1 function within tissues, rather than an endocrine function, is primarily responsible for GH-induced body growth. Le Roith et al. (2001) reviewed the essential role of the GH-IGFI axis on growth and development.
Semsarian et al. (1999) and Musaro et al. (1999) independently showed that IGF1 stimulates skeletal muscle hypertrophy and a switch to glycolytic metabolism by activating the calcium calmodulin-dependent phosphatase calcineurin (calcineurin A; 114105) and inducing the nuclear translocation of transcription factor NFATC1 (600489). Semsarian et al. (1999) found that muscle hypertrophy was suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP kinase or phosphatidylinositol-3-OH kinase pathways. Musaro et al. (1999) showed that expression of a dominant-negative calcineurin mutant also repressed myocyte differentiation and hypertrophy. Musaro et al. (1999) demonstrated that either IGF1 or activated calcineurin induces expression of transcription factor GATA2 (137295), which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of NFATC1.
Aleman et al. (1999) investigated whether the age-related decline in circulating levels of IGF1 is associated with cognitive functions that are known to decline with aging, but not with cognitive functions not sensitive to aging. Twenty-five healthy older men with well-preserved functional ability participated in the study. The authors found that IGF1 levels were significantly associated with the performances (controlled for education) on the Digit Symbol Substitution test and the Concept Shifting Task, which measure perceptual-motor and mental processing speed. Subjects with higher IGF1 levels performed better on these tests, performance on which is known to decline with aging. The authors concluded that their results supported the hypothesis that circulating IGF1 may play a role in the age-related reduction of certain cognitive functions, specifically speed of information processing.
Levels of IGF1 decrease in serum during aging, whereas amyloid-beta (104760), which is involved in the pathogenesis of Alzheimer disease (104300), accumulates in the brain. Carro et al. (2002) found high brain amyloid-beta levels at an early age in mutant mice with low circulating IGF1, and that amyloid-beta burden could be reduced in aging rats by increasing serum IGF1. They stated that this opposing relationship between serum IGF1 and brain amyloid-beta levels reflects the ability of IGF1 to induce clearance of brain amyloid-beta, probably by enhancing transport of amyloid-beta carrier proteins, such as albumin (103600) and transthyretin (176300), into the brain. This effect was antagonized by tumor necrosis factor-alpha (191160), a proinflammatory cytokine putatively involved in dementia and aging. Because IGF1 treatment of mice overexpressing mutant amyloid markedly reduced their brain amyloid-beta burden, Carro et al. (2002) considered circulating IGF1 a physiologic regulator of brain amyloid levels with therapeutic potential.
Vestergaard et al. (1999) used a cross-sectional design to study the relationships among serum IGF parameters (total serum IGF1, IGF2, and IGFBP3 (146732)), serum estradiol, and bone mineral density (BMD; 601884) stratified for potential confounders, and a longitudinal design to study the effects of hormonal replacement therapy (HRT) on IGFs and BMD. In the cross-sectional study, serum IGF1 correlated positively to distal forearm BMD and spine BMD, but not to femoral neck BMD, after stratification for age, body mass index, and other variables. In the follow-up study, HRT decreased IGF1 and IGF2, but did not influence the age-related decline in IGFBP3 significantly. Serum alkaline phosphatase and urinary hydroxyproline/creatinine ratio both decreased during HRT, whereas BMD increased compared to control values. After adjustment for age, body mass index, treatment, and other factors, IGF1 correlated positively to changes in forearm and femoral neck BMD, but not to changes in spine BMD.
Yanovski et al. (2000) studied bone mineral density and bone mineral content (BMC) in 59 African American and 59 white girls, aged 7-10 years, and found that the former group had higher plasma IGF1 and free IGF1 concentrations, which were positively correlated with BMD/BMC. Yanovski et al. (2000) also found that IGF1 was positively correlated with IGF2 in white girls (P = 0.012) but negatively correlated with IGF2 in African American girls (P = 0.015).
In a patient with insulin-dependent diabetes mellitus who pursued a typical course from age 3 to 13 years but thereafter had severe, life-threatening episodic insulin resistance, Usala et al. (1992) achieved benefit from the use of recombinant human IGF1. Schoenle et al. (1991) had successfully used the same method for treating extreme insulin resistance in Mendenhall syndrome (262190).
Retinopathy of prematurity (ROP; see 133780) is a blinding disease initiated by lack of retinal vascular growth after premature birth. Hellstrom et al. (2001) showed that lack of IGF1 in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor (VEGF; 192240), which is important for vessel development. In vitro, low levels of IGF1 prevent VEGF-induced activation of protein kinase B (AKT1; 164730), a kinase critical for endothelial cell survival. In studies of premature infants, Hellstrom et al. (2001) obtained results suggesting that if the IGF1 level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF1 is persistently low, vessels cease to grow, the maturing avascular retina becomes hypoxic, and VEGF accumulates in the vitreous. As IGF1 increases to a critical level, retinal neovascularization is triggered. These data indicated that serum IGF1 levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggested that early restoration of IGF1 in premature infants to normal levels could prevent this disease.
Simo et al. (2002) found that both free IGF1 and VEGF were increased in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy (see 603933). The elevation of IGF1 was unrelated to the elevation of VEGF in these patients. The authors suggested that VEGF is directly involved in the pathogenesis of proliferative diabetic retinopathy, whereas the precise role of free IGF1 remained to be established.
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).
Playford et al. (2000) studied the influence of IGF1 on the interaction between E-cadherin (192090) and beta-catenin (116806) in human colorectal cancer cells. Their results indicated that IGF1 causes tyrosine phosphorylation and stabilization of beta-catenin. These effects may contribute to transformation, cell migration, and a propensity for metastasis in vivo.
Hankinson et al. (1998) demonstrated a strong association between circulating IGF1 concentrations and the risk of breast cancer in premenopausal, but not postmenopausal women. In an accompanying commentary, Holly (1998) discussed the evidence that high levels of circulating IGF1 pose a risk of breast cancer in premenopausal women, and noted that a similar association has been reported for prostate cancer. Using stored sera from men followed in the Baltimore Longitudinal Study on Aging, Harman et al. (2000) investigated whether the circulating IGF1 level is an independent predictor of prostate cancer and compared its predictive value with those of IGF2 (147470), IGFBP3 (146732), and prostate-specific antigen (PSA; 176820). High IGF1 and low IGF2 were independently associated with increased risk for prostate cancer, but PSA level was a much stronger predictor of prostate cancer than either IGF1 or IGF2. The absence of a relationship of IGF1 to prostate size was inconsistent with increased ascertainment in men with large prostates as the source of greater prostate cancer risk associated with IGF1. The authors concluded that IGF2 may inhibit both prostate growth and development of prostate cancer.
Humbert et al. (2002) found that IGF1 and AKT inhibited mutant huntingtin (613004)-induced cell death and formation of intranuclear inclusions of polyQ huntingtin. AKT phosphorylated ser421 of huntingtin with 23 glutamines, and this phosphorylation reduced mutant huntingtin-induced toxicity in primary cultures of rat striatal neurons. Humbert et al. (2002) concluded that phosphorylation of huntingtin through the IGF1/AKT pathway is neuroprotective, and they hypothesized that the IGF1/AKT pathway may have a role in Huntington disease.
In rodents and humans there is a sexually dimorphic pattern of GH (139250) secretion that influences the serum concentration of IGF1. Geary et al. (2003) studied the plasma concentrations of IGF1, IGF2, IGFBP3, and GH in cord blood taken from the offspring of 987 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Cord plasma concentrations of IGF1, IGF2, and IGFBP3 were influenced by factors related to birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF1 and IGFBP3; 10.2% of the variability in cord plasma IGF1 concentration and 2.7% for IGFBP3 was explained by sex of the offspring and parity. Birth weight, length, and head circumference measurements were greater in males than females (P less than 0.001). Mean cord plasma concentrations of IGF1 and IGFBP3 were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females, but no difference was noted between the sexes for IGF2. After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF1 and IGFBP3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference.
IGF1 is contained within human platelet alpha granules, and its receptor, IGF1R, is expressed on the platelet surface. Upon stimulation, platelets secrete IGF1, thereby increasing the local IGF1 concentration, which may play a role in autocrine regulation of platelet function. Hers (2007) showed that IGF1 release potentiated agonist-induced platelet aggregation, particularly at lower agonist concentrations. IGF1 did not stimulate platelet aggregation or IGF1 secretion directly, but it activated a signaling pathway that included IGF1R, IRS1 (147545), IRS2 (600797), PI3K (see PIK3CA; 171834), and PKB (see AKT1; 164730).
Kim et al. (2007) found that IGF1 release potentiated aggregation of human platelets induced by several agonists, including ADP. IGF1 induced AKT phosphorylation through PIK3CA and mediated its potentiating effect by supplementing Gi (GNAI1; 139310) signaling through PIK3CA pathways.
The publication of Mayack et al. (2010), which reported that age-related defects in niche cells are systemically regulated and could be reversed by exposure to a young circulation or by neutralization of IGF1 in the marrow microenvironment, was retracted in its entirety by Shadrach, Kim, and Wagers. The paper was retracted due to concerns for the validity of the conclusions reported, specifically the role of osteopontin (166490)-positive niche cells in the rejuvenation of hematopoietic stem cells in aged mice. Mayack maintained that the conclusions were still valid and did not sign the retraction.
In mice, Takano et al. (2010) found that IGF1-induced phosphatidylinositol 3-kinase-Akt signaling formed a complex of nebulin (161650) and N-Wasp (605056) at the Z bands of myofibrils by interfering with glycogen synthase kinase-3-beta (GSK3B; 605004). Although N-Wasp is known to be an activator of the Arp2/3 complex (see 604221) to form branched actin filaments, the nebulin-N-Wasp complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-Wasp was required for Igf1-induced muscle hypertrophy. Takano et al. (2010) concluded that their findings presented the mechanisms of IGF1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation.
Mardinly et al. (2016) demonstrated that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP; 192320)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. Mardinly et al. (2016) identified Igf1 as one of several activity-regulated genes that are specific to Vip neurons, and demonstrate that Igf1 functions cell-autonomously in Vip neurons to increase inhibitory synaptic input onto these neurons. The authors concluded that their findings suggested that in cortical Vip neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of Igf1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.
Han et al. (2016) demonstrated that macrophages, through the release of a soluble growth factor and microvesicles, alter the type of particles engulfed by nonprofessional phagocytes (such as epithelial cells) and influence their inflammatory response. During phagocytosis of apoptotic cells or in response to inflammation-associated cytokines, macrophages released IGF1. The binding of IGF1 to its receptor on nonprofessional phagocytes redirected their phagocytosis, such that uptake of larger apoptotic cells was reduced whereas engulfment of microvesicles was increased. IGF1 did not alter engulfment by macrophages. Macrophages also released microvesicles, whose uptake by epithelial cells was enhanced by IGF1 and led to decreased inflammatory responses by epithelial cells. Consistent with these observations, deletion of IGF1 receptor in airway epithelial cells led to exacerbated lung inflammation after allergen exposure. These genetic and functional studies revealed that IGF1- and microvesicle-dependent communication between macrophages and epithelial cells can critically influence the magnitude of tissue inflammation in vivo.
In a mouse model of gliomagenesis (see, e.g., 137800), Chen et al. (2022) found that tumors preferentially developed in the olfactory bulb. Manipulating the activity of olfactory receptor neurons affected the development of glioma, and depriving the mice of olfaction suppressed glioma, supporting the association between olfactory bulb and gliomagenesis. RNA-seq and RT-PCR analyses suggested that Igf1 produced by mitral and tufted (M/T) cells in the olfactory bulb was involved in the olfaction-dependent gliomagenesis. In support of this, Chen et al. (2022) showed that M/T cell-specific knockout of Igf1 suppressed gliomagenesis in mice and demonstrated that olfaction affected glioma through the Igf pathway. The Igf1 regulation of gliomagenesis was independent of synapses, although neurogliomal synapses were known to contribute to the progression of glioma.
In a patient with severe prenatal and postnatal growth failure, sensorineural deafness, and mental retardation associated with IGF1 deficiency (608747), Woods et al. (1996) identified homozygosity for a partial deletion of the IGF1 gene (147440.0001). Bonapace et al. (2003) identified a homozygous mutation in the polyadenylation signal of the IGF1 gene (147440.0002) in a patient with IGF1 deficiency.
Rasmussen et al. (2000) considered the IGF1 and IGF1R genes as candidates for low birth weight, insulin resistance, and type II diabetes (125853). 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.
Arends et al. (2002) hypothesized that minor genetic variation in the IGF1 gene could influence pre- and postnatal growth. Three microsatellite markers located in the IGF1 gene in 124 short children who were born small for gestational age and their parents were studied. Two polymorphic markers showed transmission disequilibrium. Allele 191 of the IGF1-PCR1 marker was transmitted more frequently from parent to child and allele 198 of the 737/738 marker was transmitted less frequently from parent to child. Children carrying the 191 allele had significantly lower IGF1 levels than children not carrying this allele. Also, head circumference standard deviation score remained smaller in children with allele 191 compared to children without allele 191. The authors concluded that genetically determined low IGF1 levels may lead to a reduction in birth weight, length, and head circumference, and to persistent short stature and small head circumference in later life (proportionate small). Since low IGF1 levels are associated with type 2 diabetes and cardiovascular disease, they proposed that the IGF1 gene may provide a link between low birth weight and such diseases in later life.
Low birth weight is associated with later risk of type 2 diabetes and related disorders. Vaessen et al. (2002) studied the relationship between low birth weight and a polymorphism in the IGF1 gene that raises risk of type 2 diabetes and myocardial infarction. They recorded birth weight and obtained DNA for 463 adults. Individuals who did not have the wildtype allele of the polymorphism had a 215-gram lower birth weight than those homozygous for the wildtype allele. The data lent support to the hypothesis that genetic variation affecting fetal growth could account for the association between low birth weight and susceptibility to diabetes and cardiovascular disease in later life.
Rivadeneira et al. (2003) examined the role of a microsatellite repeat polymorphism in 1 of the promoter regions of the IGF1 gene (Arends et al., 2002; Vaessen et al., 2002) in relation to femoral bone mineral density (BMD) in elderly women and men from the Rotterdam Study. They studied 5,648 and 4,134 individuals at baseline and follow-up (approximately 2 years later), respectively. In women, baseline BMD levels were, on the average, lower in individuals without the 192-bp (wildtype) allele as compared with the homozygotes for the allele. The mean rate of BMD change from baseline to follow-up was -6.9 mg/cm2, -4.5 mg/cm2, and -2.3 mg/cm2 in noncarriers, heterozygotes, and homozygotes for the 192-bp allele, respectively (P trend = 0.03). Adjustment for age and body mass index did not essentially change this relation. No such effects were observed in men. They concluded that this promoter polymorphism or another functional polymorphism in linkage disequilibrium may be a genetic determinant of BMD levels and rate of bone loss in postmenopausal women.
In 113 small for gestational age (SGA) subjects from Haguenau, France and 174 from Gothenburg, Sweden, Johnston et al. (2003) assessed the association of IGF1 and birth size by studying SGA subphenotypes and undertaking more detailed analysis of IGF1 genetic markers. They found that IGF1 genotype was associated with the SGA phenotype, in particular with symmetrical SGA and low birth weight, and with IGF1 levels in SGA subjects. The Swedish subjects were subphenotyped according to postnatal growth (114 short SGA and 60 SGA catch-up). Association with postnatal growth was different in the 2 populations, which may reflect the power of the smaller subphenotype groups. Haplotype analysis in the Swedish short SGA subjects showed that the region of association lay between the promoter and intron 2 of the IGF1 gene. The authors concluded that these results validated the association of the IGF1 gene with birth size and refine the region of association in Swedish short SGA subjects.
Johansson et al. (2007) analyzed haplotypes and 3 haplotype-tagging SNPs in the 3-prime region of the IGF1 gene in relation to circulating levels of IGF1 in 698 control subjects from the CAncer Prostate in Sweden (CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort (NSHDC) study. In the metaanalysis, the TCC haplotype and the SNP rs6220 were associated with elevated levels of circulating IGF1 (p = 0.001 and p = less than 0.0001, respectively). Johansson et al. (2007) concluded that genetic variation in the 3-prime region of the IGF1 gene seems to influence circulating levels of IGF1, and that their observation was consistent with the hypothesis that variation in the IGF1 gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF1.
For discussion of a possible association between variation in the IGF1 gene and stature, see 606255.
Association with Myopia
For discussion of a possible association between variation in the IGF1 gene and myopia, see MYP3 (603221).
In comparing amino acid sequences of IGF1 and proinsulin, Rinderknecht and Humbel (1978) concluded that duplication of the gene of the common ancestor of the 2 genes occurred before the time of appearance of the vertebrates.
Mathews et al. (1986) studied IGF1 mRNA in the lit/lit mouse, which is believed to have a receptor-related resistance to growth hormone-releasing factor (GHRH; 139190). The liver was found to be the major site of IGF1 synthesis and the level of IGF1 mRNA was increased about 10-fold by administration of growth hormone (GH; 139250) to the lit/lit mouse. Mathews et al. (1986) showed that GH regulation was manifested in part at the transcriptional level. Growth hormone also affected the size distribution of hepatic IGF1 mRNAs. The pancreas showed the highest nonhepatic expression, but every tissue analyzed contained some IGF1 mRNA. However, in most nonhepatic tissues, IGF1 expression was not GH-dependent. Lin et al. (1993) found that the molecular basis of the 'little' (lit) mouse phenotype, which is characterized by a hypoplastic anterior pituitary gland, is a mutation in the GHRF receptor (139191).
Guler et al. (1989) found that recombinant human IGF1 had no effect on the stature of miniature poodles. They concluded that long-term infusion of recombinant human IGF1 did not stimulate growth in young miniature poodles.
To circumvent the embryonic lethality of a complete deficiency in IGF1, Lembo et al. (1996) generated mice homozygous for a site-specific insertional event that created a mutant Igf1 allele. These mice had IGF1 levels 30% of wildtype and were able to survive to adulthood. Studies revealed elevated conscious blood pressure in homozygous mice, and measurements of left ventricular contractility were increased. Adenylyl cyclase activity was enhanced in the hearts of the animals without an increase in beta-adrenergic receptor density, suggesting that cross-talk between IGF1 and beta-adrenergic signaling pathways may mediate the increased contractility. The hypertrophic response of the left ventricular myocardium in response to aortic constriction was preserved in the homozygous mice. Lembo et al. (1996) concluded that chronic alterations in IGF1 levels can selectively modulate blood pressure and left ventricular function, while not affecting adaptive myocardial hypertrophy in vivo.
Transgenic mice with a homozygous defect of the Igf1 gene (IGF1 knockout mice) have profound embryonic and postnatal growth retardation (Liu et al., 1993; Baker et al., 1993; Powell-Braxton et al., 1993).
Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. Musaro et al. (2001) generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of Igf1 that is expressed in skeletal muscle. Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathologic changes seen in other Igf1 transgenic models. Expression of Gata2 (137295), a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The observations were thought to suggest usefulness of localized expression of this transgene as a clinical strategy for the treatment of age- or disease-related muscle frailty.
In Duchenne muscular dystrophy (310200), the normal regenerative capacity of skeletal muscle cannot compensate for increased susceptibility to damage, leading to repetitive cycles of degeneration and regeneration that ultimately result in the replacement of muscle fibers with fibrotic tissue. Because IGF1 enhances muscle regeneration and protein synthetic pathways, Barton et al. (2002) hypothesized that muscle-specific expression of Igf1 could preserve muscle function in the mdx mouse model of Duchenne muscular dystrophy. Transgenic mdx mice overexpressing Igf1 in muscle showed increased muscle mass, increased force generation, reduced fibrosis, and decreased myonecrosis compared with mdx mice. In addition, signaling pathways associated with muscle regeneration and protection against apoptosis showed significantly elevated activities.
Ruberte et al. (2004) demonstrated that normoglycemic/normoinsulinemic transgenic mice overexpressing IGF1 in the retina developed most of the alterations seen in human diabetic eye disease. Eyes from 2-month-old transgenic mice showed loss of pericytes and thickening of the basement membrane of retinal capillaries. In mice 6 months and older, venule dilatation, intraretinal microvascular abnormalities, and neovascularization of the retina and vitreous cavity were observed. All of the transgenic mice developed cataracts. Ruberte et al. (2004) suggested that IGF1 has a role in the development of ocular complications in long-term diabetes.
Kurosu et al. (2005) showed that overexpression of klotho (604824) in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell surface receptor and represses intracellular signals of insulin and IGF1, an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Kurosu et al. (2005) suggested that klotho protein may function as an anti-aging hormone in mammals.
Ueki et al. (2006) created mice lacking both Insr (147670) and Ifg1r (147370) 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 Akt (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.
Sutter et al. (2007) used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genomewide scan, Sutter et al. (2007) identified a major quantitative trait locus on chromosome 15 influencing the size variation within a single breed. Second, the authors examined a genetic variation in the 15-megabase interval surrounding the quantitative trait locus in small and giant breeds and found marked evidence for a selective sweep spanning a single gene, IGF1. Sutter et al. (2007) found that a single IGF1 SNP haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
Sun et al. (2008) found that Igf1 signaling via the PI3K-Akt pathway protected cells from apoptosis induced by mouse Apop1 (APOPT1; 616003).
Pouladi et al. (2010) investigated the involvement of the IGF1 pathway in mediating the effect of huntingtin (HTT; 613004) on body weight. IGF1 expression was examined in transgenic mouse lines expressing different levels of full-length wildtype Htt (YAC18 mice), full-length mutant Htt (YAC128 and BACHD mice), and truncated mutant Htt (shortstop mice). Htt influenced body weight by modulating the IGF1 pathway. Plasma IGF1 levels correlated with body weight and Htt levels in the transgenic YAC mice expressing human HTT. The effect of Htt on IGF1 expression was independent of CAG size. No effect on body weight was observed in transgenic YAC mice expressing a truncated N-terminal Htt fragment (shortstop), indicating that full-length Htt is required for the modulation of IGF1 expression. Treatment with 17-beta-estradiol (17B-ED) lowered the levels of circulating IGF1 in mammals. Treatment of YAC128 with 17B-ED, but not placebo, reduced plasma IGF1 levels and decreased the body weight of YAC128 animals to wildtype levels. Levels of full-length Htt also influenced IGF1 expression in striatal tissues of the brain. Pouladi et al. (2010) concluded that HTT plays a novel role in influencing IGF1 expression.
Infections and inflammation are often associated with wasting of skeletal muscle and fat tissue. Schieber et al. (2015) found that C57Bl/6 mice from the Jackson Laboratories (Jax mice) exhibited wasting accompanied by anorexia, colonic inflammation, and bloody diarrhea following exposure to dextran sulfate sodium (DSS), a model for inflammatory bowel disease (see 266600). Administration of a broad-spectrum antibiotic cocktail (AVNM) had no significant impact on DSS-induced wasting in Jax mice. In contrast, C57Bl/6 mice from the University of California, Berkeley (CB mice), showed significantly less wasting when DSS was coupled with AVNM treatment. Culture of cecal bacteria revealed an AVNM-resistant E. coli O21:H+ strain in CB mice that was absent in Jax mice. Cohousing of AVNM-treated CB mice with AVNM-treated Jax mice or oral administration of E. coli O21:H+ to Jax mice conferred resistance to DSS-induced wasting. Protection from wasting was also found in mice colonized with E. coli O21:H+ that were exposed to the intestinal pathogen Salmonella Typhimurium or that were infected intranasally with the pneumonic pathogen Burkholderia thailandensis. Protection from wasting was associated with upregulation of Igf1 in muscle and white adipose tissue, but not serum, and a lack of upregulation of atrogin-1 (FBXO32; 606604) and Murf1 (TRIM63; 606131), which is crucial for muscle atrophy and typically occurs following S. Typhimurium, B. thailandensis, or DSS challenge. Maintenance of Igf1 levels was mediated by the Nlrc4 (606831) inflammasome via Il18 (600953), possibly with Il1b (147720). Schieber et al. (2015) concluded that a commensal bacterium, E. coli O21:H+, can promote tolerance to diverse diseases.
In a boy with intrauterine and postnatal growth failure, sensorineural deafness, and mental retardation associated with insulin-like growth factor-1 deficiency (608747), Woods et al. (1996) identified a homozygous deletion of exons 4 and 5 of the IGF1 gene. Direct sequencing showed that IGF1 exon 3 continued directly into exon 6, completely skipping exons 4 and 5, resulting in a mature IGF1 peptide truncated from 70 amino acids to 25 amino acids, followed by an additional out-of-frame nonsense sequence of 8 residues and a premature stop codon. Both of the boy's parents, who were first cousins once removed, were heterozygous for the deletion and showed short stature with borderline low levels of IGF1.
In a boy with intrauterine and postnatal growth failure, sensorineural deafness, and mental retardation associated with insulin-like growth factor I deficiency (608747), Bonapace et al. (2003) identified a homozygous T-A transversion in the polyadenylation signal in the 3-prime untranslated region of IGF1 exon 6. The patient's parents, who were related, were heterozygous for the mutation. Bonapace et al. (2003) determined that the mutation disrupts the correct consensus sequence for the normal polyadenylation pathway and deregulates the splicing and maturation of the mRNA. Direct sequencing of the mutant product showed that the initial part of exon 6 is fused to a protein kinase gene (ARK5, or KIAA0537; 608130), resulting in the skipping of the codifying sequence of exon 6. Bonapace et al. (2003) noted that the findings demonstrated the importance of IGF1 in pre- and postnatal growth, as well the role of IGF1 in brain development.
In a 55-year-old male with insulin-like growth factor I deficiency (608747), the first child of consanguineous parents, Walenkamp et al. (2005) found a homozygous G-to-A transition in the IGF1 gene changing valine-44 to methionine (V44M). Functional analysis demonstrating 90-fold reduced affinity of the mutant IGF1 for the IGF1 receptor proved the inactivating nature of the mutation. The phenotype included severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF1 in utero. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, agrees with the hypothesis that IGF1 secretion in childhood is mainly GH-dependent. IGF1 haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.
Aleman, A., Verhaar, H. J. J., De Haan, E. H. F., De Vries, W. R., Samson, M. M., Drent, M. L., Van Der Veen, E. A., Koppeschaar, H. P. F. Insulin-like growth factor-I and cognitive function in healthy older men. J. Clin. Endocr. Metab. 84: 471-475, 1999. [PubMed: 10022403] [Full Text: https://doi.org/10.1210/jcem.84.2.5455]
Arends, N., Johnston, L., Hokken-Koelega, A., Van Duijn, C., De Ridder, M., Savage, M., Clark, A. Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J. Clin. Endocr. Metab. 87: 2720-2724, 2002. [PubMed: 12050240] [Full Text: https://doi.org/10.1210/jcem.87.6.8673]
Baker, J., Liu, J.-P., Robertson, E. J., Efstratiadis, A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73-82, 1993. [PubMed: 8402902]
Barton, E. R., Morris, L., Musaro, A., Rosenthal, N., Sweeney, H. L. Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J. Cell Biol. 157: 137-147, 2002. [PubMed: 11927606] [Full Text: https://doi.org/10.1083/jcb.200108071]
Bianda, T., Glatz, Y., Bouillon, R., Froesch, E. R., Schmid, C. Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults. J. Clin. Endocr. Metab. 83: 81-87, 1998. [PubMed: 9435420] [Full Text: https://doi.org/10.1210/jcem.83.1.4484]
Bonapace, G., Concolino, D., Formicola, S., Strisciuglio, P. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. (Letter) J. Med. Genet. 40: 913-917, 2003. [PubMed: 14684690] [Full Text: https://doi.org/10.1136/jmg.40.12.913]
Bowcock, A., Sartorelli, V. Polymorphism and mapping of the IGF1 gene, and absence of association with stature among African Pygmies. Hum. Genet. 85: 349-354, 1990. [PubMed: 2394448] [Full Text: https://doi.org/10.1007/BF00206760]
Brissenden, J. E., Ullrich, A., Francke, U. Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature 310: 781-784, 1984. [PubMed: 6382023] [Full Text: https://doi.org/10.1038/310781a0]
Carro, E., Trejo, J. L., Gomez-Isla, T., LeRoith, D., Torres-Aleman, I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nature Med. 8: 1390-1397, 2002. [PubMed: 12415260] [Full Text: https://doi.org/10.1038/nm1202-793]
Chen, P., Wang, W., Liu, R., Lyu, J., Zhang, L., Li, B., Qiu, B., Tian, A., Jiang, W., Ying, H., Jing, R., Wang, Q., Zhu, K., Bai, R., Zeng, L., Duan, S., Liu, C. Olfactory sensory experience regulates gliomagenesis via neuronal IGF1. Nature 606: 550-556, 2022. [PubMed: 35545672] [Full Text: https://doi.org/10.1038/s41586-022-04719-9]
Copeland, K. C., Underwood, L. E., Van Wyk, J. J. Induction of immunoreactive somatomedin C in human serum by growth hormone: dose-response relationships and effect on chromatographic profiles. J. Clin. Endocr. Metab. 50: 690-697, 1980. [PubMed: 7189195] [Full Text: https://doi.org/10.1210/jcem-50-4-690]
Daughaday, W. H., Hall, K., Raben, M. S., Salmon, W. D., Jr., van den Brande, L. J., van Wyk, J. J. Somatomedin: proposed designation for sulphation factor. Nature 235: 107 only, 1972. [PubMed: 4550398] [Full Text: https://doi.org/10.1038/235107a0]
Geary, M. P. P., Pringle, P. J., Rodeck, C. H., Kingdom, J. C. P., Hindmarsh, P. C. Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. J. Clin. Endocr. Metab. 88: 3708-3714, 2003. [PubMed: 12915659] [Full Text: https://doi.org/10.1210/jc.2002-022006]
Guler, H.-P., Binz, K., Eigenmann, E., Jaggi, S., Zimmermann, D., Zapf, J., Froesch, E. R. Small stature and insulin-like growth factors: prolonged treatment of mini-poodles with recombinant human insulin-like growth factor I. Acta Endocr. 121: 456-464, 1989. [PubMed: 2508389] [Full Text: https://doi.org/10.1530/acta.0.1210456]
Han, C. Z., Juncadella, I. J., Kinchen, J. M., Buckley, M. W., Klibanov, A. L., Dryden, K., Onengut-Gumuscu, S., Erdbrugger, U., Turner, S. D., Shim, Y. M., Tung, K. S., Ravichandran, K. S. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539: 570-574, 2016. [PubMed: 27820945] [Full Text: https://doi.org/10.1038/nature20141]
Hankinson, S. E., Willett, W. C., Colditz, G. A., Hunter, D. J., Michaud, D. S., Deroo, B., Rosner, B., Speizer, F. E., Pollak, M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351: 1393-1396, 1998. [PubMed: 9593409] [Full Text: https://doi.org/10.1016/S0140-6736(97)10384-1]
Harman, S. M., Metter, E. J., Blackman, M. R., Landis, P. K., Carter, H. B. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer. J. Clin. Endocr. Metab. 85: 4258-4265, 2000. [PubMed: 11095464] [Full Text: https://doi.org/10.1210/jcem.85.11.6990]
Hellstrom, A., Perruzzi, C., Ju, M., Engstrom, E., Hard, A.-L., Liu, J.-L., Albertsson-Wikland, K., Carlsson, B., Niklasson, A., Sjodell, L., LeRoith, D., Senger, D. R., Smith, L. E. H. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc. Nat. Acad. Sci. 98: 5804-5808, 2001. [PubMed: 11331770] [Full Text: https://doi.org/10.1073/pnas.101113998]
Hers, I. Insulin-like growth factor-2 potentiates platelet activation via the IRS/PI3K-alpha pathway. Blood 110: 4243-4252, 2007. [PubMed: 17827393] [Full Text: https://doi.org/10.1182/blood-2006-10-050633]
Holly, J. Insulin-like growth factor-I and new opportunities for cancer prevention. Lancet 351: 1373-1375, 1998. [PubMed: 9593403] [Full Text: https://doi.org/10.1016/S0140-6736(05)79438-1]
Hoppener, J. W. M., de Pagter-Holthuizen, P., Geurts van Kessel, A. H. M., Jansen, M., Kittur, S. D., Antonarakis, S. E., Lips, C. J. M., Sussenbach, J. S. The human gene encoding insulin-like growth factor I is located on chromosome 12. Hum. Genet. 69: 157-160, 1985. [PubMed: 2982726] [Full Text: https://doi.org/10.1007/BF00293288]
Humbert, S., Bryson, E. A., Cordelieres, F. P., Connors, N. C., Datta, S. R., Finkbeiner, S., Greenberg, M. E., Saudou, F. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt. Dev. Cell 2: 831-837, 2002. [PubMed: 12062094] [Full Text: https://doi.org/10.1016/s1534-5807(02)00188-0]
Jansen, M., van Schaik, F. M. A., Ricker, A. T., Bullock, B., Woods, D. E., Gabbay, K. H., Nussbaum, A. L., Sussenbach, J. S., Van den Brande, J. L. Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature 306: 609-611, 1983. [PubMed: 6358902] [Full Text: https://doi.org/10.1038/306609a0]
Johansson, M., McKay, J. D., Wiklund, F., Rinaldi, S., Verheus, M., van Gils, C. H., Hallmans, G., Balter, K., Adami, H.-O., Gronberg, H., Stattin, P., Kaaks, R. Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels. J. Clin. Endocr. Metab. 92: 4820-4826, 2007. [PubMed: 17911177] [Full Text: https://doi.org/10.1210/jc.2007-0887]
Johnston, L. B., Dahlgren, J., Leger, J., Gelander, L., Savage, M. O., Czernichow, P., Wikland, K. A., Clark, A. J. L. Association between insulin-line growth factor I (IGF-I) polymorphisms, circulating IGF-I, and pre- and postnatal growth in two European small for gestational age populations. J. Clin. Endocr. Metab. 88: 4805-4810, 2003. [PubMed: 14557458] [Full Text: https://doi.org/10.1210/jc.2003-030563]
Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866, 1990. [PubMed: 1975791] [Full Text: https://doi.org/10.1093/genetics/125.4.855]
Kim, S., Garcia, A., Jackson, S. P., Kunapuli, S. P. Insulin-like growth factor-1 regulates platelet activation through PI3-K-alpha isoform. Blood 110: 4206-4213, 2007. [PubMed: 17827385] [Full Text: https://doi.org/10.1182/blood-2007-03-080804]
Kim, S.-W., Lajara, R., Rotwein, P. Structure and function of a human insulin-like growth factor-1 gene promoter. Molec. Endocr. 5: 1964-1972, 1991. [PubMed: 1791841] [Full Text: https://doi.org/10.1210/mend-5-12-1964]
Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C. R., Rosenblatt, K. P., Kuro-o, M. Suppression of aging in mice by the hormone klotho. Science 309: 1829-1833, 2005. [PubMed: 16123266] [Full Text: https://doi.org/10.1126/science.1112766]
Lambooij, A. C., van Wely, K. H. M., Lindenbergh-Kortleve, D. J., Kuijpers, R. W. A. M., Kliffen, M., Mooy, C. M. Insulin-like growth factor-I and its receptor in neovascular age-related macular degeneration. Invest. Ophthal. Vis. Sci. 44: 2192-2198, 2003. [PubMed: 12714661] [Full Text: https://doi.org/10.1167/iovs.02-0410]
Le Bouc, Y., Dreyer, D., Jaeger, F., Binoux, M., Sondermeyer, P. Complete characterization of the human IGF-I nucleotide sequence isolated from a newly constructed adult liver cDNA library. FEBS Lett. 196: 108-112, 1986. [PubMed: 2935423] [Full Text: https://doi.org/10.1016/0014-5793(86)80223-x]
Le Roith, D., Scavo, L., Butler, A. What is the role of circulating IGF-I? Trends Endocr. Metab. 12: 48-52, 2001. [PubMed: 11167121] [Full Text: https://doi.org/10.1016/s1043-2760(00)00349-0]
Lembo, G., Rockman, H. A., Hunter, J. J., Steinmetz, H., Koch, W. J., Ma, L., Printz, M. P., Ross, J., Jr., Chien, K. R., Powell-Braxton, L. Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency. J. Clin. Invest. 98: 2648-2655, 1996. [PubMed: 8958230] [Full Text: https://doi.org/10.1172/JCI119086]
Li, C. H., Yamashiro, D., Gospodarowicz, D., Kaplan, S. L., Van Vliet, G. Total synthesis of insulin-like growth factor I (somatomedin C). Proc. Nat. Acad. Sci. 80: 2216-2220, 1983. [PubMed: 6572973] [Full Text: https://doi.org/10.1073/pnas.80.8.2216]
Lin, S.-C., Lin, C. R., Gukovsky, I., Lusis, A. J., Sawchenko, P. E., Rosenfeld, M. G. Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature 364: 208-213, 1993. [PubMed: 8391647] [Full Text: https://doi.org/10.1038/364208a0]
Liu, J.-P., Baker, J., Perkins, A. S., Robertson, E. J., Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59-72, 1993. [PubMed: 8402901]
Mardinly, A. R., Spiegel, I., Patrizi, A., Centofante, E., Bazinet, J. E., Tzeng, C. P., Mandel-Brehm, C., Harmin, D. A., Adesnik, H., Fagiolini, M., Greenberg, M. E. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531: 371-375, 2016. [PubMed: 26958833] [Full Text: https://doi.org/10.1038/nature17187]
Mathews, L. S., Norstedt, G., Palmiter, R. D. Regulation of insulin-like growth factor I gene expression by growth hormone. Proc. Nat. Acad. Sci. 83: 9343-9347, 1986. [PubMed: 3467309] [Full Text: https://doi.org/10.1073/pnas.83.24.9343]
Mayack, S. R., Shadrach, J. L., Kim, F. S., Wagers, A. J. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 463: 495-500, 2010. Note: Retraction: Nature 467: 872 only, 2010. [PubMed: 20110993] [Full Text: https://doi.org/10.1038/nature08749]
Morton, C. C., Byers, M. G., Nakai, H., Bell, G. I., Shows, T. B. Human genes for insulin-like growth factors I and II and epidermal growth factor are located on 12q22-q24.1, 11p15, and 4q25-q27, respectively. Cytogenet. Cell Genet. 41: 245-249, 1986. [PubMed: 3486749] [Full Text: https://doi.org/10.1159/000132237]
Morton, C., Rall, L., Bell, G., Shows, T. Human insulin-like growth factor-1 (IGF1) is encoded at 12q22-q24.1, and insulin-like growth factor-2 (IGF2) is at 11p15. (Abstract) Cytogenet. Cell Genet. 40: 703 only, 1985.
Mullis, P. E., Patel, M. S., Brickell, P. M., Hindmarsh, P. C., Brook, C. G. D. Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: genetic linkage of the insulin-like growth factor I gene at chromosome 12q23 to the disease in a subgroup of these patients. Clin. Endocr. 34: 265-274, 1991. [PubMed: 1879059] [Full Text: https://doi.org/10.1111/j.1365-2265.1991.tb03765.x]
Musaro, A., McCullagh, K. J. A., Naya, F. J., Olson, E. N., Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400: 581-585, 1999. [PubMed: 10448862] [Full Text: https://doi.org/10.1038/23060]
Musaro, A., McCullagh, K., Paul, A., Houghton, L., Dobrowolny, G., Molinaro, M., Barton, E. R., Sweeney, H. L., Rosenthal, N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genet. 27: 195-200, 2001. [PubMed: 11175789] [Full Text: https://doi.org/10.1038/84839]
Playford, M. P., Bicknell, D., Bodmer, W. F., Macaulay, V. M. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc. Nat. Acad. Sci. 97: 12103-12108, 2000. [PubMed: 11035789] [Full Text: https://doi.org/10.1073/pnas.210394297]
Pouladi, M. A., Xie, Y., Skotte, N. H., Ehrnhoefer, D. E., Graham, R. K., Kim, J. E., Bissada, N., Yang, X. W., Paganetti, P., Friedlander, R. M., Leavitt, B. R., Hayden, M. R. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum. Molec. Genet. 19: 1528-1538, 2010. [PubMed: 20097678] [Full Text: https://doi.org/10.1093/hmg/ddq026]
Powell-Braxton, L., Hollingshead, P., Warburton, C., Dowd, M., Pitts-Meek, S., Dalton, D., Gillett, N., Stewart, T. A. IGF-I is required for normal embryonic growth in mice. Genes Dev. 7: 2609-2617, 1993. [PubMed: 8276243] [Full Text: https://doi.org/10.1101/gad.7.12b.2609]
Rapp, R., Deger, A., Blum, W., Koch, R., Weber, U. Characterization of the protein which binds insulin-like growth factor in human serum. Europ. J. Biochem. 172: 421-425, 1988. [PubMed: 2450744] [Full Text: https://doi.org/10.1111/j.1432-1033.1988.tb13904.x]
Rasmussen, S. K., Lautier, C., Hansen, L., Echwald, S. M., Hansen, T., Ekstrom, C. T., Urhammer, S. A., Borch-Johnsen, K., Grigorescu, F., Smith, R. J., Pedersen, O. Studies of the variability of the genes encoding the insulin-like growth factor I receptor and its ligand in relation to type 2 diabetes mellitus. J. Clin. Endocr. Metab. 85: 1606-1610, 2000. [PubMed: 10770205] [Full Text: https://doi.org/10.1210/jcem.85.4.6494]
Rinderknecht, E., Humbel, R. E. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J. Biol. Chem. 253: 2769-2776, 1978. [PubMed: 632300]
Rivadeneira, F., Houwing-Duistermaat, J. J., Vaessen, N., Vergeer-Drop, J. M., Hofman, A., Pols, H. A. P., Van Duijn, C. M., Uitterlinden, A. G. Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam study. J. Clin. Endocr. Metab. 88: 3878-3884, 2003. [PubMed: 12915683] [Full Text: https://doi.org/10.1210/jc.2002-021813]
Rosenfeld, R. G. Insulin-like growth factors and the basis of growth. New Eng. J. Med. 349: 2184-2186, 2003. [PubMed: 14657423] [Full Text: https://doi.org/10.1056/NEJMp038156]
Rotwein, P., Pollock, K. M., Didier, D. K., Krivi, G. G. Organization and sequence of the human insulin-like growth factor I gene: alternative RNA processing produces two insulin-like growth factor I precursor peptides. J. Biol. Chem. 261: 4828-4832, 1986. [PubMed: 2937782]
Rotwein, P. Two insulin-like growth factor I messenger RNAs are expressed in human liver. Proc. Nat. Acad. Sci. 83: 77-81, 1986. [PubMed: 3455760] [Full Text: https://doi.org/10.1073/pnas.83.1.77]
Ruberte, J., Ayuso, E., Navarro, M., Carretero, A., Nacher, V., Haurigot, V., George, M., Llombart, C., Casellas, A., Costa, C., Bosch, A., Bosch, F. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J. Clin. Invest. 113: 1149-1157, 2004. [PubMed: 15085194] [Full Text: https://doi.org/10.1172/JCI19478]
Schieber, A. M. P., Lee, Y. M., Chang, M. W., Leblanc, M., Collins, B., Downes, M., Evans, R. M., Ayres, J. S. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 350: 558-563, 2015. [PubMed: 26516283] [Full Text: https://doi.org/10.1126/science.aac6468]
Schoenle, E. J., Zenobi, P. D., Torresani, T., Werder, E. A., Zachmann, M., Froesch, E. R. Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. Diabetologia 34: 675-679, 1991. [PubMed: 1955101] [Full Text: https://doi.org/10.1007/BF00400998]
Semsarian, C., Wu, M.-J., Ju, Y.-K., Marciniec, T., Yeoh, T., Allen, D. G., Harvey, R. P., Graham, R. M. Skeletal muscle hypertrophy is mediated by a Ca(2+)-dependent calcineurin signalling pathway. Nature 400: 576-581, 1999. [PubMed: 10448861] [Full Text: https://doi.org/10.1038/23054]
Simo, R., Lecube, A., Segura, R. M., Garcia Arumi, J., Hernandez, C. Free insulin growth factor-1 and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am. J. Ophthal. 134: 376-382, 2002. [PubMed: 12208249] [Full Text: https://doi.org/10.1016/s0002-9394(02)01538-6]
Sjogren, K., Liu, J.-L., Blad, K., Skrtic, S., Vidal, O., Wallenius, V., LeRoith, D., Tornell, J., Isaksson, O. G. P., Jansson, J.-O., Ohlsson, C. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Nat. Acad. Sci. 96: 7088-7092, 1999. [PubMed: 10359843] [Full Text: https://doi.org/10.1073/pnas.96.12.7088]
Smith, P. J., Spurrell, E. L., Coakley, J., Hinds, C. J., Ross, R. J. M., Krainer, A. R., Chew, S. L. An exonic splicing enhancer in human IGF-I pre-mRNA mediates recognition of alternative exon 5 by the serine-arginine protein splicing factor-2/alternative splicing factor. Endocrinology 143: 146-154, 2002. [PubMed: 11751603] [Full Text: https://doi.org/10.1210/endo.143.1.8598]
Sun, X., Yasuda, O., Takemura, Y., Kawamoto, H., Higuchi, M., Baba, Y., Katsuya, T., Kukuo, K., Ogihara, T., Rakugi, H. Akt activation prevents Apop-1-induced death of cells. Biochem. Biophys. Res. Commun. 377: 1097-1101, 2008. [PubMed: 18977203] [Full Text: https://doi.org/10.1016/j.bbrc.2008.10.109]
Sussenbach, J. S., Steenbergh, P. H., Holthuizen, P. Structure and expression of the human insulin-like growth factor genes. Growth Regul. 2: 1-9, 1992. [PubMed: 1486331]
Sutter, N. B., Bustamante, C. D., Chase, K., Gray, M. M., Zhao, K., Zhu, L., Padhukasahasram, B., Karlins, E., Davis, S., Jones, P. G., Quignon, P., Johnson, G. S., and 9 others. A single IGF1 allele is a major determinant of small size in dogs. Science 316: 112-115, 2007. Note: Erratum: Science 316: 1284 only, 2007. [PubMed: 17412960] [Full Text: https://doi.org/10.1126/science.1137045]
Svoboda, M. E., Van Wyk, J. J., Klapper, D. G., Fellows, R. E., Grissom, F. E., Schleuter, R. J. Purification of somatomedin-C from human plasma: chemical and biological properties, partial sequence analysis, and relationship to other somatomedins. Biochemistry 19: 790-797, 1980. [PubMed: 7188854] [Full Text: https://doi.org/10.1021/bi00545a027]
Takano, K., Watanabe-Takano, H., Suetsugu, S., Kurita, S., Tsujita, K., Kimura, S., Karatsu, T., Takenawa, T., Endo, T. Nebulin and N-WASP cooperate to cause IGF-1-induced sarcomeric actin filament formation. Science 330: 1536-1540, 2010. [PubMed: 21148390] [Full Text: https://doi.org/10.1126/science.1197767]
Taylor, B. A., Grieco, D. Localization of the gene encoding insulin-like growth factor I on mouse chromosome 10. Cytogenet. Cell Genet. 56: 57-58, 1991. [PubMed: 2004558] [Full Text: https://doi.org/10.1159/000133046]
Tricoli, J. V., Rall, L. B., Scott, J., Bell, G. I., Shows, T. B. Insulin-like growth factor genes: chromosome organization and association with disease. (Abstract) Am. J. Hum. Genet. 36: 121S only, 1984.
Tricoli, J. V., Rall, L. B., Scott, J., Bell, G. I., Shows, T. B. Localization of insulin-like growth factor genes to human chromosomes 11 and 12. Nature 310: 784-786, 1984. [PubMed: 6382024] [Full Text: https://doi.org/10.1038/310784a0]
Ueki, K., Okada, T., Hu, J., Liew, C. W., Assmann, A., Dahlgren, G. M., Peters, J. L., Shackman, J. G., Zhang, M., Artner, I., Satin, L. S., Stein, R., Holzenberger, M., Kennedy, R. T., Kahn, C. R., Kulkarni, R. N. Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nature Genet. 38: 583-588, 2006. [PubMed: 16642022] [Full Text: https://doi.org/10.1038/ng1787]
Ullrich, A., Berman, C. H., Dull, T. J., Gray, A., Lee, J. M. Isolation of the human insulin-like growth factor I gene using a single synthetic DNA probe. EMBO J. 3: 361-364, 1984. [PubMed: 6232133] [Full Text: https://doi.org/10.1002/j.1460-2075.1984.tb01812.x]
Usala, A.-L., Madigan, T., Burguera, B., Sinha, M. K., Caro, J. F., Cunningham, P., Powell, J. G., Butler, P. C. Treatment of insulin-resistant diabetic ketoacidosis with insulin-like growth factor I in an adolescent with insulin-dependent diabetes. New Eng. J. Med. 327: 853-857, 1992. [PubMed: 1508245] [Full Text: https://doi.org/10.1056/NEJM199209173271205]
Vaessen, N., Janssen, J. A., Heutink, P., Hofman, A., Lamberts, S. W. J., Oostra, B. A., Pols, H. A. P., van Duijn, C. M. Association between genetic variation in the gene for insulin-like growth factor-1 and low birthweight. Lancet 359: 1036-1037, 2002. [PubMed: 11937187] [Full Text: https://doi.org/10.1016/s0140-6736(02)08067-4]
Van Wyk, J. J., Svoboda, M. E., Underwood, L. E. Evidence from radioligand assays that somatomedin-C and insulin-like growth factor-I are similar to each other and different from other somatomedins. J. Clin. Endocr. Metab. 50: 206-208, 1980. [PubMed: 7350184] [Full Text: https://doi.org/10.1210/jcem-50-1-206]
Vestergaard, P., Hermann, A.P., Orskov, H., Mosekilde, L., The Danish Osteoporosis Prevention Study. Effect of sex hormone replacement on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal women participating in the Danish osteoporosis prevention study. J. Clin. Endocr. Metab. 84: 2286-2290, 1999. [PubMed: 10404791] [Full Text: https://doi.org/10.1210/jcem.84.7.5865]
Walenkamp, M. J. E., Karperien, M., Pereira, A. M., Hilhorst-Hofstee, Y., van Doorn, J., Chen, J. W., Mohan, S., Denley, A., Forbes, B., van Duyvenvoorde, H. A., van Thiel, S. W., Sluimers, C. A., Bax, J. J., de Laat, J. A. P. M., Breuning, M. B., Romijn, J. A., Wit, J. M. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J. Clin. Endocr. Metab. 90: 2855-2864, 2005. [PubMed: 15769976] [Full Text: https://doi.org/10.1210/jc.2004-1254]
Woods, K. A., Camacho-Hubner, C., Savage, M. O., Clark, A. J. L. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New Eng. J. Med. 335: 1363-1367, 1996. [PubMed: 8857020] [Full Text: https://doi.org/10.1056/NEJM199610313351805]
Yakar, S., Liu, J.-L., Stannard, B., Butler, A., Accili, D., Sauer, B., LeRoith, D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Nat. Acad. Sci. 96: 7324-7329, 1999. [PubMed: 10377413] [Full Text: https://doi.org/10.1073/pnas.96.13.7324]
Yang-Feng, T. L., Brissenden, J. E., Ullrich, A., Francke, U. Sub-regional localization of human genes for insulin-like growth factors I (IGF1) and II (IGF2) by in situ hybridization. (Abstract) Cytogenet. Cell Genet. 40: 782 only, 1985.
Yanovski, J. A., Sovik, K. N., Nguyen, T. T., Sebring, N. G. Insulin-like growth factors and bone mineral density in African American and white girls. J. Pediat. 137: 826-832, 2000. [PubMed: 11113840] [Full Text: https://doi.org/10.1067/mpd.2000.109151]
Zhu, J., Kahn, C. R. Analysis of a peptide hormone-receptor interaction in the yeast two-hybrid system. Proc. Nat. Acad. Sci. 94: 13063-13068, 1997. [PubMed: 9371800] [Full Text: https://doi.org/10.1073/pnas.94.24.13063]