The IGF2 gene provides instructions for making a protein called insulin-like growth factor 2. This protein plays an essential role in growth and development before birth. Studies suggest that insulin-like growth factor 2 promotes the growth and division (proliferation) of cells in many different tissues. Although the IGF2 gene is highly active during fetal development, it is much less active after birth.
People inherit one copy of most genes from their mother and one copy from their father. Both copies are typically active, or "turned on," in cells. However, the activity of the IGF2 gene depends on which parent it was inherited from. Only the copy inherited from a person's father (the paternally inherited copy) is active; the copy inherited from the mother (the maternally inherited copy) is not active. This parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting.
IGF2 is part of a cluster of genes on the short (p) arm of chromosome 11 that undergoes genomic imprinting. Another gene in this cluster, H19, is also involved in growth and development. A nearby region of DNA known as imprinting center 1 (IC1) or the H19 differentially methylated region (H19 DMR) controls the parent-specific genomic imprinting of both the IGF2 and H19 genes. The IC1 region undergoes a process called methylation, which is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. Methylation, which occurs during the formation of an egg or sperm cell, is a way of marking or "stamping" the parent of origin. The IC1 region is normally methylated only on the paternally inherited copy of chromosome 11.
Health Conditions Related to Genetic Changes
Beckwith-Wiedemann syndrome, a condition characterized by overgrowth and other signs and symptoms that affect many parts of the body, can result from changes that affect the IC1 region. In some people with this condition, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Because the IC1 region controls the genomic imprinting of the IGF2 and H19 genes, this abnormality disrupts the regulation of both genes. Specifically, abnormal methylation of the IC1 region leads to increased IGF2 gene activity and a loss of H19 gene activity in many tissues. An increase in IGF2 gene activity, which promotes growth, and a loss of H19 gene activity, which normally restrains growth, together lead to overgrowth in people with Beckwith-Wiedemann syndrome.
In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the IC1 region. Like abnormal methylation, these deletions alter the activity of the IGF2 and H19 genes.More About This Health Condition
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Changes in methylation of the IC1 region are also responsible for some cases of Russell-Silver syndrome, a disorder characterized by slow growth before and after birth. The changes are different than those seen in Beckwith-Wiedemann syndrome (described above) and have the opposite effect on growth.
In Russell-Silver syndrome, the paternally inherited copy of the IC1 region often has too few methyl groups attached (hypomethylation). Hypomethylation of the IC1 region leads to a loss of IGF2 gene activity and increased activity of the H19 gene in many tissues. A loss of IGF2 gene activity, which normally promotes growth, and an increase in H19 gene activity, which restrains growth, together lead to poor growth and short stature in people with Russell-Silver syndrome.More About This Health Condition
Changes in methylation of the IC1 region have also been found in some cases of Wilms tumor, a rare form of kidney cancer that occurs almost exclusively in children.
In some people with Wilms tumor, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Abnormal methylation of the IC1 region leads to a loss of H19 gene activity, which normally restrains cell growth, and increased IGF2 gene activity in kidney cells. Increased IGF2 gene activity raises insulin-like growth factor 2 protein production, which likely stimulates the growth of tumor cells in the kidney and prevents damaged cells from being destroyed. As this mechanism is similar to the one that causes Beckwith-Wiedemann syndrome (described above), it is thought that individuals with Wilms tumor caused by changes in IC1 methylation may later be diagnosed with Beckwith-Wiedemann syndrome.
In most cases, abnormal methylation of IC1 and subsequent changes in IGF2 and H19 gene activity are somatic, which means that they are acquired during a person's lifetime and present only in some tissues. Rarely, these changes are germline, which means they are present in all of the body's cells.More About This Health Condition
Increased activity of the IGF2 gene has been associated with many types of cancer. Normally, the IGF2 gene undergoes genomic imprinting and only the copy inherited from a person's father is active. In some cancers, however, both the paternally inherited and the maternally inherited copies of the gene are active, increasing the amount of insulin-like growth factor 2 that cells can produce. This phenomenon, known as loss of imprinting (LOI), occurs during a person's lifetime in cells that ultimately give rise to cancer. An increased amount of insulin-like growth factor 2 may stimulate the growth of tumor cells and prevent damaged cells from being destroyed.
Loss of imprinting of the IGF2 gene has been identified in several types of cancer. In some cases these cancers occur without any other related health problems, in other cases they occur in people with Beckwith-Wiedemann syndrome (described above). These include cancer of blood-forming cells (leukemia), a cancer of muscle tissue called rhabdomyosarcoma, a form of liver cancer called hepatoblastoma, and cancers of the breast, prostate, lung, and colon. In some types of cancer, increased levels of insulin-like growth factor 2 are associated with the growth and spread of tumors.
Other Names for This Gene
- insulin-like growth factor 2
- insulin-like growth factor 2 (somatomedin A)
- insulin-like growth factor II
- insulin-like growth factor type 2
- putative insulin-like growth factor II associated protein
- somatomedin A
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
- Abu-Amero S, Monk D, Frost J, Preece M, Stanier P, Moore GE. The genetic aetiology of Silver-Russell syndrome. J Med Genet. 2008 Apr;45(4):193-9. doi: 10.1136/jmg.2007.053017. Epub 2007 Dec 21. Citation on PubMed
- Al-Hussain T, Ali A, Akhtar M. Wilms tumor: an update. Adv Anat Pathol. 2014 May;21(3):166-73. doi: 10.1097/PAP.0000000000000017. Citation on PubMed
- Bergman D, Halje M, Nordin M, Engstrom W. Insulin-like growth factor 2 in development and disease: a mini-review. Gerontology. 2013;59(3):240-9. doi: 10.1159/000343995. Epub 2012 Dec 20. Citation on PubMed
- Cerrato F, Sparago A, Verde G, De Crescenzo A, Citro V, Cubellis MV, Rinaldi MM, Boccuto L, Neri G, Magnani C, D'Angelo P, Collini P, Perotti D, Sebastio G, Maher ER, Riccio A. Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumour. Hum Mol Genet. 2008 May 15;17(10):1427-35. doi: 10.1093/hmg/ddn031. Epub 2008 Feb 1. Citation on PubMed
- Eggermann T. Silver-Russell and Beckwith-Wiedemann syndromes: opposite (epi)mutations in 11p15 result in opposite clinical pictures. Horm Res. 2009 Apr;71 Suppl 2:30-5. doi: 10.1159/000192433. Epub 2009 Apr 29. Citation on PubMed
- Kaneda A, Wang CJ, Cheong R, Timp W, Onyango P, Wen B, Iacobuzio-Donahue CA, Ohlsson R, Andraos R, Pearson MA, Sharov AA, Longo DL, Ko MS, Levchenko A, Feinberg AP. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20926-31. doi: 10.1073/pnas.0710359105. Epub 2007 Dec 17. Citation on PubMed or Free article on PubMed Central
- Livingstone C. IGF2 and cancer. Endocr Relat Cancer. 2013 Oct 24;20(6):R321-39. doi: 10.1530/ERC-13-0231. Print 2013 Dec. Citation on PubMed
- MacFarland SP, Duffy KA, Bhatti TR, Bagatell R, Balamuth NJ, Brodeur GM, Ganguly A, Mattei PA, Surrey LF, Balis FM, Kalish JM. Diagnosis of Beckwith-Wiedemann syndrome in children presenting with Wilms tumor. Pediatr Blood Cancer. 2018 Oct;65(10):e27296. doi: 10.1002/pbc.27296. Epub 2018 Jun 22. Citation on PubMed or Free article on PubMed Central
- Pickard A, McCance DJ. IGF-Binding Protein 2 - Oncogene or Tumor Suppressor? Front Endocrinol (Lausanne). 2015 Feb 27;6:25. doi: 10.3389/fendo.2015.00025. eCollection 2015. Citation on PubMed or Free article on PubMed Central
- Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet. 2004 Sep;36(9):958-60. doi: 10.1038/ng1410. Epub 2004 Aug 15. Citation on PubMed
- Tian F, Yourek G, Shi X, Yang Y. The development of Wilms tumor: from WT1 and microRNA to animal models. Biochim Biophys Acta. 2014 Aug;1846(1):180-7. doi: 10.1016/j.bbcan.2014.07.003. Epub 2014 Jul 11. Review. Citation on PubMed
- Turner JT, Brzezinski J, Dome JS. Wilms Tumor Predisposition. 2003 Dec 19 [updated 2022 Mar 24]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK1294/ Citation on PubMed