Alternative titles; symbols
HGNC Approved Gene Symbol: IGF2
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:2,129,117-2,149,566 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Silver-Russell syndrome 3 | 616489 | Autosomal dominant | 3 |
IGF2 is a protein hormone involved in the regulation of cell proliferation, growth, migration, differentiation, and survival. In contrast with IGF1 (147440), which is preferentially expressed after birth and is produced almost exclusively in liver, IGF2 is preferentially expressed in early embryonic and fetal development and in a wide variety of somatic tissues. Adult IGF2 expression occurs in liver and in epithelial cells lining the surface of the brain. IGF2 is present in circulation and can be detected in plasma, with circulating IGF2 levels highest in fetal circulation. IGF2 is imprinted and is expressed exclusively from the paternal allele except in adult liver and central nervous system, where it is expressed biallelically. The H19/IGF2-imprinting control region (ICR1; 616186), which is located between the H19 (103280) and IGF2 genes, coordinates imprinted expression of IGF2 and H19, which is expressed exclusively from the maternal allele (review by Bergman et al., 2013).
Using a sequence that is identical in human IGF1 and IGF2 as probe, Bell et al. (1984) cloned IGF2 from an adult liver cDNA library. The deduced 180-amino acid prepro-IGF2 protein contains an N-terminal signal sequence followed by the mature peptide and a C-terminal extension called the E domain. Both the signal sequence and E domains are proteolytically removed to generate the mature 67-amino acid peptide.
Using a buffalo rat liver Igf2 cDNA as probe, Dull et al. (1984) cloned human IGF2 from a fetal liver cDNA library. The putative 180-amino acid IGF2 precursor starting at met-24 has a calculated molecular mass of 20.1 kD.
Using the coding region of human liver IGF2 as probe, Shen et al. (1988) cloned IGF2 from a human placenta cDNA library. They identified 4 variants in placenta that differed from the liver variant only in their 5-prime ends; the coding sequences appeared to be identical. Northern blot analysis using exon-specific probes revealed transcripts of 6.0, 4.9, 3.2, and 2.2 kb in placenta. The 5-prime end of the 4.9-kb variant differed from those of the liver transcript and the other placenta transcripts.
De Pagter-Holthuizen et al. (1988) stated that a 5.3-kb mRNA is initiated at IGF2 exon 1 and is expressed in adult liver, and a 6.0-kb transcript is initiated at exon 4 and is expressed in fetal tissues and in several adult non-liver tissues. They determined that a 2.2-kb transcript is also initiated at exon 4, and a 4.8-kb transcript is initiated at exon 4B. The 4.8-kb transcript was expressed in most fetal tissues and in several adult non-liver tissues. Northern blot analysis using the 3-prime UTR probe revealed a novel 1.8-kb transcript in adult and fetal liver and in fetal adrenal gland, skeletal muscle, and kidney, but not in fetal lung or brain. Sequence analysis showed that this transcript derived from exon 7 of the IGF2 gene. In vitro translation resulted in expression of an 84-amino acid peptide with an apparent molecular mass of 8.3 kD.
Monk et al. (2006) identified 5 IGF2 transcripts that differ only in their 5-prime untranslated regions. Northern blot analysis detected transcripts driven by the P1 promoter, which they called P1 transcripts, in liver only. Variable expression of P0 transcripts was detected in most tissues examined except brain and early placenta; highest expression was found in fetal skeletal muscle, term placenta, and kidney. In contrast, the mouse P0 transcript was expressed only in placenta. Monk et al. (2006) also identified 2 spliced read-through transcripts that contain exons from the upstream INS2 gene (176730) fused to IGF2 exons. See (176730) for further information on these transcripts, which the authors called INSIGF.
De Pagter-Holthuizen et al. (1988) determined that the IGF2 gene extends over 30 kb and contains 8 exons: 5 noncoding exons (exons 1-4 and 4B) followed by 3 coding exons (exons 5-7). Exon 7 also contains a long 3-prime UTR. Promoter regions precede exons 1, 4 and 4B, resulting in alternative transcripts. The promoter regions preceding exons 4 and 4B contain several promoter elements such as TATA and CCAAT boxes and SP1 (189906) recognition sites.
Monk et al. (2006) determined that the IGF2 gene contains 9 exons; only exons 7 through 9 contain the coding region. IGF2 has 5 promoter regions, P1, P0, P2, P3, and P4, located in exons 1, 2, 4, 5, and 6, respectively. The P1 promoter has no ortholog in mouse. The IGF2 gene also contains 2 Alu repeats and 4 CpG islands; the final CpG island overlaps the coding region of exon 9.
Using cDNA probes in the analysis of somatic cell hybrids, Brissenden et al. (1984) and Tricoli et al. (1984) independently assigned IGF2 to 11p15-p11. By analysis of human-Chinese hamster somatic cell hybrids, de Pagter-Holthuizen et al. (1985) assigned the IGF2 gene to chromosome 11. The location on chromosome 11 of this locus, structurally homologous to the proinsulin locus (also on 11), is noteworthy. The assignment of IGF1 to chromosome 12 adds to the known homology of 11 and 12. By comparing the restriction enzyme cleavage maps of the IGF2 and INS genes, including their flanking regions and hybridization with an IGF2 cDNA probe, Bell et al. (1985) concluded that these 2 genes are adjacent to one another. They have the same polarity and are separated by 12.6 kb of intergenic DNA that includes a dispersed middle repetitive Alu sequence. The order of the genes is 5-prime--INS--IGF2--3-prime.
By in situ hybridization, Reeve et al. (1985) mapped the IGF2 gene to 11p14.1, close to the WAGR locus.
By in situ hybridization, Morton et al. (1986) assigned IGF2 to 11p15.
Function of IGF2
Scott et al. (1985) pointed out that Wilms tumor (194070) is histologically indistinguishable from the early stages of kidney development. In 12 sporadic cases of Wilms tumor, Scott et al. (1985) found that expression of the IGF2 gene was markedly increased relative to adult tissues, but was comparable to the level of expression in several fetal tissues including kidney, liver, adrenal, and striated muscle. Although this may merely reflect the stage of tumor differentiation, the possibility that IGF2 is involved in the transformation process was raised. In 4 cases of Wilms tumor, Reeve et al. (1985) found that transcripts of IGF2 were highly elevated as compared with adjacent normal kidney. They proposed that IGF2 is the (or a) transforming gene in Wilms tumor.
Daughaday et al. (1988) demonstrated that recurrent hypoglycemia in a woman with leiomyosarcoma was the result of secretion of IGF II by the tumor.
Burgisser et al. (1991) studied the function of 3 experimentally produced mutants of IGF II expressed in NIH3T3 cells.
The major fetal IGF II promoter, as defined in transient transfection assays, is a region spanning from nucleotides -295 to +135, relative to the transcription start site. Drummond et al. (1992) demonstrated that the WT1 gene product (607102) binds to multiple sites in this region and functions as a potent repressor of IGF II transcription in vivo. Maximal repression was dependent on the presence of WT1 binding sites on each side of the transcriptional initiation site. These findings provided a molecular basis for overexpression of IGF II in Wilms tumors and suggested that WT1 negatively regulates blastemal cell proliferation by limiting the production of a fetal growth factor in the developing vertebrate kidney.
Nielsen et al. (1999) found that IMP1 (IGF2BP1; 608288), IMP2 (IGF2BP2; 608289), and IMP3 (IGF2BP3; 608259) associate specifically with the 5-prime UTR of the human 6.0-kb IGF2 leader 3 mRNA, suggesting a role for IMPs in the physiologic regulation of IGF2 production. By mobility shift analysis, they determined that IGF2 leader 3 mRNA contains at least 6 binding sites for IMP1; no binding sites were found on IGF2 leader 4 mRNA. IMP1 competed with PTB (600693) for IGF2 leader 3 mRNA binding in a Mg(2+)-dependent manner, and binding was mutually exclusive. PTB was the predominant species at low Mg(2+) concentrations, while IMP1 was predominant at higher Mg(2+) concentrations. IMP1 inhibited translation from a leader 3 reporter mRNA in vivo.
Brisken et al. (2002) found that prolactin (PRL; 176760) induced Igf2 mRNA and Igf2 induced cyclin D1 (CCND1; 168461) protein expression in mouse mammary epithelial cultures. Alveologenesis was retarded in both Igf2-deficient cells and cyclin D1-deficient cells. Igf2 and prolactin receptor (PRLR; 176761) mRNAs colocalized in mammary epithelium. Brisken et al. (2002) concluded that IGF2 is a mediator of prolactin-induced alveologenesis and that prolactin, IGF2, and cyclin D1 are components of a developmental pathway in mammary gland.
Chen et al. (2011) reported that, in the rat, administering IGF2 significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF2, which requires the transcription factor CCAAT/enhancer-binding protein-beta (CEBPB; 189965) and is essential for memory consolidation. Furthermore, injections of recombinant IGF2 into the hippocampus after either training or memory retrieval significantly enhanced memory retention and prevented forgetting. To be effective, IGF2 needs to be administered within a sensitive period of memory consolidation. IGF2-dependent memory enhancement requires IGF2 receptors (IGF2R; 147280), new protein synthesis, the function of activity-regulated cytoskeletal-associated protein, and glycogen-synthase kinase-3 (606784). Moreover, it correlates with a significant activation of synaptic GSK3-beta (605004) and increased expression of GluR1 (138248) alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptor subunits. In hippocampal slices, IGF2 promoted IGF2 receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, Chen et al. (2011) concluded that IGF2 may represent a novel target for cognitive enhancement therapies.
Yang et al. (2017) found that acute deletion of the Kruppel-associated box-zinc finger (KRAB-ZNF) gene Zfp568 (ZNF568; 617566) in mouse embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) resulted in inappropriate activation of the placenta-specific P0 transcript of Igf2, but not other Igf2 transcripts. Chronic deletion of Zfp568 led to reactivation not only of the P0 transcript, but also the P1, P2, and P3 transcripts. Chromatin immunoprecipitation sequencing showed binding of Zfp568 to the Igf2-P0 promoter in ESCs and TSCs, and the Igf2-P0 promoter had a strong histone H3 (see 602810) lys9 (H3K9) trimethylation signal that was lost upon Zfp568 deletion. Deletion of the KRAB-ZNF corepressors Setdb1 (604396) and Trim28 (601742) also resulted in derepression of Igf2-P0 and loss of trimethylated H3K9. Mutation of the Zfp568-binding site in Igf2-P0 or the KRAB domain of Zfp568 resulted in increased Igf2-P0 expression in ESCs. Yang et al. (2017) concluded that Zfp568 maintains a heterochromatin state at the Igf2-P0 promoter by direct interaction with its binding site.
Intrauterine Growth Restriction
Qiu et al. (2005) found that aberrant processing of pro-IGF2 by PC4 (PCSK4; 600487) may be a cause of intrauterine growth restriction (IUGR), a leading cause of perinatal mortality. PC4 cleaved pro-IGF2 to generate the intermediate processed form, IGF2 (1-102). Mature IGF2 (1-67), likely resulting from further processing by carboxypeptidase s (see CPE, 114855), is capable of activating invasive trophoblast cells through AKT (see AKT1; 164730) phosphorylation. Inhibition of PC4 by a PC4-specific inhibitor blocked pro-IGF2 processing and reduced trophoblast cell migration. Serum samples of women carrying IUGR fetuses displayed elevated levels of pro-IGF2 compared to normal pregnant women. Qiu et al. (2005) suggested that abnormal processing of IGF2 by PC4 may be a mechanism involved in the pathophysiology of fetoplacental growth restriction.
Using DNA microarrays to compare gene expression patterns in normal human placenta with those in other tissues, Sood et al. (2006) found that several genes involved in growth and tissue remodeling were expressed at relatively higher levels in the villus sections of placenta compared with other tissues. These included GPC3 (300037), CDKN1C (600856), and IGF2. The GPC3 and CDKN1C genes are mutated in patients with Simpson-Golabi-Behmel syndrome (312870) and Beckwith-Wiedemann syndrome (130650), respectively, both fetal-placental overgrowth syndromes. In contrast, loss of IGF2 is associated with fetal growth restriction in mice. The relatively higher expression of genes that both promote and suppress growth suggested to Sood et al. (2006) tight and local regulation of the pathways that control placental development.
Imprinting of IGF2
Lighten et al. (1997) demonstrated that IGF2 is parentally imprinted during human preimplantation development. They used an ApaI polymorphism at the 3-prime UTR of the IGF2 gene to distinguish between mRNA derived from each copy of the gene in fertilized embryos at the 4- and 8-cell stage. They found that at the 8-cell stage and beyond only the paternal IGF2 gene was expressed.
Although the neighboring genes IGF2 and H19 share an enhancer, H19 is expressed only from the maternal allele, and IGF2 only from the paternally inherited allele. The region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting of both H19 and IGF2 (Thorvaldsen et al., 1998). Bell and Felsenfeld (2000) showed that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF (604167). Methylation of CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. Bell and Felsenfeld (2000) suggested that it controls imprinting of IGF2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. Bell and Felsenfeld (2000) concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary.
The unmethylated imprinted-control region (ICR) acts as a chromatin boundary that blocks the interaction of IGF2 with enhancers that lie 3-prime of H19 (Webber et al., 1998; Hark and Tilghman, 1998). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of IGF2 paternally. Hark et al. (2000) demonstrated, using transgenic mice and tissue culture, that the unmethylated ICRs from mouse and human H19 exhibit enhancer-blocking activity. They showed that CTCF binds to several sites in the unmethylated ICR that are essential for enhancer blocking. Consistent with this model, CTCF binding is abolished by DNA methylation.
The mouse Igf2 locus is a complex genomic region that produces multiple transcripts from alternative promoters. Expression at this locus is regulated by parental imprinting. However, despite the existence of putative imprinting control elements in the Igf2 upstream region, imprinted transcriptional repression is abolished by null mutations at the linked H19 locus. To clarify the extent to which the Igf2 upstream region contains autonomous imprinting control elements, Moore et al. (1997) performed functional and comparative analyses of the region in the mouse and human. They reported the existence of multiple, overlapping imprinted (maternally repressed) sense and antisense transcripts that are associated with a tandem repeat in the mouse Igf2 upstream region. The regions flanking the repeat exhibited tissue-specific parental allelic methylation patterns, suggesting the existence of tissue-specific control elements in the upstream region. Studies in H19-null mice indicated that both parental allelic methylation and monoallelic expression of the upstream transcripts depends on an intact H19 gene acting in cis. The homologous region in human IGF2 is structurally conserved, with the significant exception that it does not contain a tandem repeat. The results supported the proposal that tandem repeats act to target methylation to imprinted genetic loci.
Constancia et al. (2000) established a differentially methylated region (DMR) silencer, DMR1, as a local imprinting control element for mouse Igf2 that does not affect H19. H19-dependent loss of imprinting of IGF2 had been described in Wilms tumor and the Beckwith-Wiedemann syndrome. In hepatoblastoma and a sizable proportion of BWS patients, however, LOI of IGF2 was observed without alterations in H19 imprinting, implying H19-independent pathways to LOI. The results of Constancia et al. (2000) provided evidence that such a pathway exists. Mutations in DMR1, or deficiencies in putative repressor molecules that bind the unmethylated DMR1, could lead to LOI with considerable impact in disease and cancer.
Du et al. (2003) confirmed the existence of insulators in the H19 DMR and reported 2 insulators in the IGF2 gene. The authors demonstrated binding of the zinc finger protein CTCF in vitro to all insulator sequences detected.
Monk et al. (2006) found that IGF2 transcripts from the P0 promoter, like those from all other IGF2 promoters, were paternally expressed in all fetal and placental tissues examined. Maternal methylation of the IGF2 P0 promoter was found in all tissues.
Venkatraman et al. (2013) demonstrated upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term hematopoietic stem cells and their downregulation upon hematopoietic stem cell activation and proliferation. A DMR upstream of H19, serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR675, which restricts Igf1r (147370) expression (Keniry et al., 2012). Venkatraman et al. (2013) demonstrated that conditional deletion of the maternal but not the paternal H19 DMR reduces adult hematopoietic stem cell quiescence, a state required for long-term maintenance of hematopoietic stem cells, and compromised hematopoietic stem cell function. Maternal-specific H19 DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (602681), an inactive form, from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation, and eventual exhaustion of hematopoietic stem cells. Mechanistically, maternal-specific H19 DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR675. Similarly, genetic inactivation of Igf1r partly rescues the H19 DMR deletion phenotype. Venkatraman et al. (2013) concluded that their work established a role for this form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells.
For further information on the H19/IGF2-imprinting control region, see ICR1 (616186).
Gene-Environment Interaction
Prenatal famine in humans has been associated with various consequences in later life, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Tobi et al. (2009) investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to war-time famine in the Netherlands from 1944 to 1945. Methylation of INSIGF (see 176730), the alternately spliced read-through transcripts of INS and IGF2, was lower among 60 individuals who were periconceptionally exposed to the famine compared to 60 of their unexposed same-sex sibs, whereas methylation of IL10 (124092), LEP (164160), ABCA1 (600046), GNASAS (610540) and MEG3 (605636) was higher than control. A significant interaction with sex was observed for INSIGF, LEP and GNASAS. When methylation of 8 representative loci was compared between 62 individuals exposed late in gestation and 62 of their unexposed sibs, methylation was different for GNASAS in both men and women, and LEP methylation was different in men only. Tobi et al. (2009) concluded that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure, and that these changes may depend on the sex of the exposed individual and the gestational timing of the exposure.
Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter IGF2 and its inhibitor, mannose 6-phosphate (M6P)/IGF2R, respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. Williams et al. (2012) showed that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. Williams et al. (2012) proposed that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.
Obesity
Le Stunff et al. (2001) studied the parental transmission of alleles at the insulin locus to offspring with early-onset obesity in children of central European and North African descent. A variable number tandem repeat (VNTR) polymorphism upstream of the insulin gene is associated with variations in the expression of INS and the nearby gene encoding IGF2. The class I allele of this VNTR is 26 to 63 repeats, while the class III allele is 141 to 209 repeats. Le Stunff et al. (2001) found an excess of paternal transmission of class I VNTR alleles to obese children: children who inherited a class I allele from their father (but not those inheriting it from their mother) had a relative risk of early onset obesity of 1.8. Due to the frequency of class I alleles in this population, this risk concerns 65 to 70% of all infants. Le Stunff et al. (2001) concluded that increased in utero expression of paternal INS or IGF2 due to the class I INS VNTR allele may predispose offspring to postnatal fat deposition.
In a cohort of more than 2,500 middle-aged Caucasoid males, Gaunt et al. (2001) identified 3 single-nucleotide polymorphisms (SNPs) in the IGF2 gene (147470.0001-147470.0003) that were associated with body mass index (BMI).
Metabolic Syndrome
Rodriguez et al. (2004) haplotyped 2,743 adult males at the IGF2-INS (176730)-TH (191290) region and related haplotypes to body weight and composition, blood pressure, and plasma triglycerides. Haplotype *5 protected against obesity; haplotype *6 was associated with raised plasma triglyceride levels. Haplotype *4, defined by the IGF2 ApaI (G), INS class III VNTR, and TH01 9.3 alleles, was associated with significantly higher fat mass and percentage fat, and with significantly higher diastolic blood pressure. Haplotype *8 showed similar magnitude of effects as *4. Haplotypes *4, *6, and *8 were the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displayed unique features in all 3 genes. The authors proposed that the long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, may predispose to the metabolic syndrome features of elevated blood pressure, fat mass, or triglyceride level, therefore appearing more frequently in type 2 diabetic (125853), polycystic ovary syndrome (see 184700), and coronary heart disease cases.
Silver-Russell Syndrome 3
In a 4-generation family segregating severe growth restriction and distinctive facies (GRDF; 616489), Begemann et al. (2015) performed exome sequencing and identified a heterozygous nonsense mutation in the IGF2 gene (S64X; 147470.0004) that segregated fully with the disorder. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.
See 616186 for information on the association of hypomethylation in the H19/IGF2-imprinting control region and Silver-Russell syndrome (SRS; 180860).
In an 18-month-old Japanese boy with Silver-Russell syndrome (SRS), Yamoto et al. (2017) identified heterozygosity for a de novo paternally inherited indel mutation in the IGF2 gene (147470.0005).
In a 13-year-old Chinese boy with SRS, who was negative for ICR1 (616186) hypomethylation and for mutation in the IGF1 and IGF1R (147370), Liu et al. (2017) identified heterozygosity for a de novo missense mutation in the IGF2 gene (G34D; 616489.0006) that arose on the paternal allele and was not found in public variant databases.
From a cohort of 192 patients with a suspected diagnosis of SRS, Abi Habib et al. (2018) identified 2 unrelated patients with heterozygous de novo mutations in the IGF2 gene. Experiments in Hep3b cells demonstrated that HMGA2 (600698) and PLAG1 (603026) both positively regulate expression of the IGF2 promoter P3, independently and via an HMGA2-PLAG1-IGF2 pathway. The authors noted that disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects.
In a 4-year-old Australian Aboriginal girl with SRS, Poulton et al. (2018) identified heterozygosity for a de novo splicing mutation in the IGF2 gene (616489.0007), occurring on the paternal allele.
In a 5.5-year-old German boy with SRS, Rockstroh et al. (2019) identified heterozygosity for a de novo 1-bp deletion in the IGF2 gene (616489.0008) that arose on the paternal allele. Functional analysis showed markedly reduced activation of IGF1R with the mutant compared to wildtype.
Masunaga et al. (2020) studied 5 unrelated Japanese patients who had heterozygous de novo mutations in the IGF2 gene, including 1 splice site and 4 missense mutations, that were not found in in-house or public variant databases. Reviewing previously reported IGF2 mutations, the authors noted that the mutations were widely distributed on IGF2 with no mutation hot spots or ethnic differences.
Beckwith-Wiedemann Syndrome
Rainier et al. (1993) reported relaxation (or loss) of imprinting of IGF2 in sporadic Wilms tumor (194070); the same was reported in a group of patients with Beckwith-Wiedemann syndrome (BWS; 130650) by Weksberg et al. (1993). The loss of imprinting was demonstrated by finding biallelic expression of the locus.
Brown et al. (1996) described evidence of alteration of imprinting in a BWS family with an inversion, inv(11)(p11.2;p15.5). They demonstrated that the inversion led to biallelic expression of IGF2 and altered DNA replication patterns in the IGF2 region. The H19 imprinting in affected individuals was normal, suggesting an H19-independent pathway to biallelic IGF2 transcription. DNA methylation in IGF2 remained monoallelic, suggesting to Brown et al. (1996) that the mutation caused by the translocation had uncoupled allele-specific methylation from gene expression.
Morison et al. (1996) reported constitutional relaxation of imprinting of IGF2 in 4 children with somatic overgrowth who did not show signs of Beckwith-Wiedemann syndrome. All 4 children showed nephromegaly and 2 developed Wilms tumors. Imprinting of IGF2 was examined using a nested RNA PCR assay in which a portion of the gene encompassing the exon 9 ApaI/AvaII restriction site polymorphism was amplified. In all 4 patients, IGF2 was found to be biallelically expressed. In 28 informative children and 22 informative normal adults, this assay showed monoallelic expression of IGF2. Studies carried out in 13 children from informative families confirmed that the paternally derived allele was expressed. Disruption of H19 methylation was observed in 3 of the 4 patients. On the basis of their findings, Morison et al. (1996) proposed that IGF2 overgrowth disorder represents a distinct entity and that Beckwith-Wiedemann syndrome is an extreme manifestation of this disorder.
Murrell et al. (2004) screened the conserved sequences between human and mouse DMRs of the IGF2 gene for variants in order to find other genetic predispositions to BWS. Four SNPs were found in DMR0 (T123C, G358A, T382G, and A402G) which occurred in 3 of 16 possible haplotypes: TGTA, CATG, and CAGA. DNA samples from a cohort of sporadic BWS patients and healthy controls were genotyped for the DMR0 SNPs. There was a significant increase in the frequency of the CAGA haplotype and a significant decrease in the frequency of the CATG haplotype in the patient cohort compared to controls. These associations were still significant in a BWS subgroup with KvDMR1 loss of methylation, suggesting that the G allele at T382G SNP (CAGA haplotype) may be associated with loss of methylation at KvDMR1. Murrell et al. (2004) proposed either a genetic predisposition to loss of methylation or interactions between genotype and epigenotype that impinge on the disease phenotype.
See 616186 for information on hypermethylation and variation in the H19/IGF2-imprinting control region and BWS.
Loss of IGF2 Imprinting and Tumor Development
IGF2 is a mitogen for many cell types and an important modulator of muscle growth and differentiation. The gene is widely expressed during prenatal development and its activity is regulated by genomic imprinting, the gene being inactive on the chromosome inherited from the mother in most normal tissues. Pedone et al. (1994) showed that monoallelic expression of IGF2 is conserved in normal adult muscle tissue, whereas 2 or more copies of active IGF2 alleles, arising by either relaxation of imprinting or duplication of the active allele, were found in 9 of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histologic subtype. This observation, together with the finding that IGF2 acts as an autocrine growth factor for rhabdomyosarcoma cells, indicates that acquisition of a double dosage of active IGF2 gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise predominantly in rhabdomyosarcomas, since Pedone et al. (1994) found only 1 case of partial reactivation of the maternal IGF2 allele out of 7 leiomyosarcomas tested.
Ogawa et al. (1993) examined the imprinting of the IGF2 gene in 10 normal kidney samples from children with renal embryonal neoplasms. In kidney samples from 9 children with normal growth profiles, IGF2 mRNA was transcribed monoallelically, consistent with normal imprinting of the gene. On the other hand, in 1 child who had generalized somatic overgrowth, IGF2 was transcribed from both alleles in her kidney, peripheral blood leukocytes, and Wilms tumor. These findings suggested that a defect in genomic imprinting can occur constitutionally, leading to growth abnormalities and predisposition to Wilms tumor. The patient was a 9-year-old Pacific Islander female (the report was from New Zealand) who at 2.5 years had treatment of Wilms tumor. The tumor showed epithelial and rhabdomyoblastic differentiation and there was an adjacent large intralobar nephrogenic rest. Karyotype was normal. Both height and weight had remained 3 to 4 standard deviations above the mean for age. Her growth excess was proportionate and there were no features typical of Beckwith-Wiedemann syndrome or other syndromal causes of excessive growth. The parents had normal height. The patient's plasma growth hormone and serum IGF1 and IGF2 were normal.
Loss of imprinting, an epigenetic alteration affecting the IGF2 gene, is found in normal colonic mucosa of about 30% of colorectal cancer (114500) patients, but it is found in only 10% of healthy individuals. In a pilot study to investigate the utility of loss of imprinting as a marker of colorectal cancer risk, Cui et al. (2003) evaluated 172 patients at a colonoscopy clinic. The adjusted odds ratio for loss of imprinting in lymphocytes was 5.15 for patients with a positive family history (95% confidence interval, 1.70 to 16.96; P = 0.002), 3.46 for patients with adenomas (95% confidence interval, 1.14 to 11.37; P = 0.026), and 21.7 for patients with colorectal cancer (95% confidence interval, 3.48 to 153.6; P = 0.0005). Loss of imprinting can be assayed with a DNA-based blood test, and Cui et al. (2003) concluded that it may be a valuable predictive marker of an individual's risk for colorectal cancer.
Evidence of the role of IGF2 in BWS was presented by Sun et al. (1997). They introduced Igf2 transgenes into the mouse genome by using embryonic stem (ES) cells and thereby caused transactivation of the endogenous Igf2 gene. The consequent overexpression of Igf2 resulted in most of the symptoms of Beckwith-Wiedemann syndrome, including prenatal overgrowth, polyhydramnios, fetal and neonatal lethality, disproportionate organ overgrowth including tongue enlargement, and skeletal abnormalities. This was presented as evidence that IGF2 overexpression is a key determinant of BWS.
DeChiara et al. (1991) produced targeted disruption of the Igf2 gene in mice by homologous recombination in ES cells. Transmission of this mutation through the male germline resulted in heterozygous progeny that were growth deficient. In contrast, when the disrupted gene was transmitted maternally, the heterozygous offspring were phenotypically normal. Homozygous mutants were indistinguishable in appearance from growth-deficient heterozygous sibs. Nuclease protection and in situ hybridization analyses of the transcripts from the wildtype and mutated alleles indicated that only the paternal allele was expressed in embryos, while the maternal allele was silent. An exception was found in the choroid plexus and leptomeninges, where both alleles were transcriptionally active. These results demonstrated that IGF II is indispensable for normal embryonic growth and that the gene is subject to tissue-specific parental imprinting. Zhang and Tycko (1992) referred to this as monoallelic expression.
Both Nezer et al. (1999) and Jeon et al. (1999) demonstrated a quantitative trait locus (QTL) in the region of IGF2 that had a major effect on muscle mass and fat deposition in pigs. They found that, as in man and mouse, IGF2 is imprinted and expressed exclusively from the paternal allele in several tissues in pigs.
Jones et al. (2001) described a 12-kb deletion of a region 5-prime of the imprinting control region (ICR) that was hypersensitive to nuclease digestion in chromatin. Its deletion resulted in a biallelic decrease in expression of Igf2, but not H19 (103280), in the brains of transgenic mice, consistent with the hypothesis that it encodes a positive regulatory element. In addition, the deletion resulted in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue. Lastly, the reduction in Igf2 expression in the adult mouse was accompanied by increased fat deposition and occasional obesity. Overweight animals were hypophagic, suggesting that Igf2 affects fat metabolism rather than feeding behavior in adult mice.
Zaina et al. (2002) showed that homozygosity for a disrupted Igf2 allele in mice lacking apolipoprotein E (APOE; 107741), a widely used animal model of atherosclerosis, results in aortic lesions that are about 80% smaller and contain about 50% less proliferating cells compared with mice lacking ApoE alone. They also found that mice carrying an IGF2 transgene specifically targeted to smooth muscle cells developed aortic focal intimal masses, suggesting atherogenic activity of Igf2.
Constancia et al. (2002) demonstrated that a deletion from the Igf2 gene of a transcript (P0) specifically expressed in the labyrinthine trophoblast of the murine placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. Constancia et al. (2002) also showed that passive permeability for nutrients of the mutant placenta was decreased, but that secondary active placental amino acid transport was initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. While this observation may be restricted to the mouse, Constancia et al. (2002) concluded that their study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting.
Lopes et al. (2003) examined regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline-specific methylation was reprogrammed after fertilization in 2 differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, the authors found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination.
A paternally expressed QTL affecting muscle growth, fat deposition, and size of the heart in pigs maps to the IGF2 region. Van Laere et al. (2003) demonstrated that this QTL is caused by a nucleotide substitution in intron 3 of IGF2. The mutation occurs in evolutionarily conserved CpG island that is hypomethylated in skeletal muscle. The mutation abrogates in vitro interaction with a nuclear factor, probably a repressor, and pigs inheriting the mutation from their sire have a 3-fold increase in IGF2 mRNA expression in postnatal muscle. Van Laere et al. (2003) concluded that their study established a causal relationship between a single-basepair substitution in a noncoding region and a QTL effect.
To investigate the role of LOI of Igf2 in intestinal tumorigenesis, Sakatani et al. (2005) created a mouse model of Igf2 loss of imprinting by crossing female H19 heterozygote mice with male Apc/Min heterozygote mice. Mice with loss of imprinting developed twice as many intestinal tumors as did control littermates. These mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with loss of imprinting. Sakatani et al. (2005) concluded that altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.
Kaneda and Feinberg (2005) reviewed the study of Sakatani et al. (2005), showing that a mouse model of LOI of the Igf2 gene, which shows aberrant activation of the normally silent maternal allele, modifies the risk of intestinal neoplasia caused by mutations of the adenomatous polyposis coli (Apc) gene. This increased risk corresponds to the apparent increased risk of colorectal cancer in patients with LOI of IGF2. The model suggests that preexisting epigenetic alterations in normal cells increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells, providing a novel idea for cancer risk management.
Coan et al. (2008) found that both Igf2-null and placental-specific knockout mice had fetal and placental growth restrictions compared to wildtype. However, in Igf2-null mice, fetal and placental growth restrictions occurred concurrently in gestation, whereas placental growth restriction preceded fetal growth restriction in mice with placenta-specific Igf2 knockout. Moreover, Igf2-null mice displayed disproportionate growth of the structural compartments of the placenta. In contrast, mice with placenta-specific Igf2 knockout displayed proportionate effects on the compartments and diffusional exchange characteristics, and ability of the placenta to increase its transport efficiency, leading to a less severe growth restriction. These data indicated that the placental phenotype depended on the degree of Igf2 gene ablation and the interplay between placental and fetal Igf2 in mice.
Gaunt et al. (2001) identified 3 single-nucleotide polymorphisms (SNPs) in IGF2 which were associated with body mass index (BMI) in a cohort of over 2,500 middle-aged Caucasoid males: 6815A-T in the IGF2 P1 promoter (p = 0.00012, n = 2394), 1156C-T in intron 2 (147470.0002) (p = 0.017, n = 1567), and 1926C-G in the 3-prime untranslated region (147470.0003) (p = 0.0062, n = 1872). There was strong pairwise linkage disequilibrium between the previously BMI-associated 3-prime untranslated region ApaI polymorphism and 1926C-G sites, but not other combinations. Univariately 6815A-T, 1156T-C, and ApaI explained 1.03%, 1.02%, and 0.67%, respectively, of the variation in BMI. Multiway analysis of variance (ANOVA) models showed that 6815A-T and 1156T-C explained a further 0.4% and 0.8% of the variation beyond that accounted for by ApaI and the association of 1926C-G with BMI disappeared after adjustment. The total proportion of BMI variance explained by this model was 2.25%, leading the authors to suggest that IGF2 genetic variation may be a significant determinant of body weight in middle-aged males. Bachner-Melman et al. (2005) tested nonclinical subjects from 376 families for these 3 IGF2 SNPs and for eating disorders as assessed by the Eating Attitudes Test. Highly significant association was observed between the ApaI G allele (which they termed 820G) and scores on the Eating Attitudes Test overall and each of its subscales (bulimia, dieting, and oral control). In addition, a significant association was observed between this polymorphism and BMI. The IGF2 ApaI G allele, which predisposes to weight gain, may contribute to constant dieting that leads to eating disorders in predisposed individuals.
See 147470.0001 and Gaunt et al. (2001).
See 147470.0001 and Gaunt et al. (2001).
In affected members of a 4-generation family with severe growth restriction and distinctive facies (SRS3; 616489), Begemann et al. (2015) identified heterozygosity for a c.191C-A transversion (c.191C-A, NM_001127598.2) in exon 3 of the IGF2 gene, resulting in a ser64-to-ter (S64X) substitution. Affected individuals inherited the mutation from their healthy fathers, and it originated from the healthy paternal grandmother. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.
In an 18-month-old Japanese boy with Silver-Russell syndrome (SRS3; 616489), Yamoto et al. (2017) identified heterozygosity for a de novo indel variant (c.110_117delinsAGGTAA, NM_000612.5) in exon 2 of the IGF2 gene, causing a frameshift predicted to result in a premature termination codon (Leu37GlnfsTer31). Methylation analysis indicated that the variant occurred on the paternal allele.
In HEK293 cells transfected with the c.110_117delinsAGGTAA mutant protein, Rockstroh et al. (2019) detected no mutant IGF2, consistent with nonsense-mediated mRNA decay.
In a 13-year-old Chinese boy with Silver-Russell syndrome (SRS3; 616489), Liu et al. (2017) identified heterozygosity for a de novo c.101G-A transition (c.101G-A, NM_000612) in the IGF2 gene, resulting in a gly34-to-asp (G34D) substitution at a highly conserved residue adjacent to the first alpha-helix. The mutation arose on the paternal allele and was not found in the dbSNP, 1000 Genomes Project, ESP, or ExAC databases.
In a 4-year-old Australian Aboriginal girl with Silver-Russell syndrome (SRS3; 616489), Poulton et al. (2018) identified heterozygosity for a de novo splicing mutation (c.157+3A-C, NM_000612.5) that arose on the paternal allele and was not found in clinical or population databases.
In a 5.5-year-old German boy with Silver-Russell syndrome (SRS3; 616489), Rockstroh et al. (2019) identified heterozygosity for a de novo 1-bp deletion (c.195delC, NM_000612) in exon 3 of the IGF2 gene, causing a frameshift predicted to result in a premature termination codon (Ile66SerfsTer93). The mutation was shown to have arisen on the paternal allele. Functional analysis in transfected HEK293 cells showed only marginal activation of IGF1R (147370) with the mutant compared to wildtype.
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