The PLAGL1 gene provides instructions for making a member of a protein family called zinc finger proteins. Zinc finger proteins are involved in many cellular functions. These proteins each contain one or more short regions called zinc finger domains, which include a specific pattern of protein building blocks (amino acids) and one or more charged atoms of zinc (zinc ions).
Zinc finger proteins attach (bind) primarily to DNA. In most cases, they attach to regions near certain genes and turn the genes on and off as needed. Proteins that bind to DNA and regulate the activity of particular genes are known as transcription factors. Some zinc finger proteins can also bind to other molecules, including RNA (a chemical cousin of DNA) and proteins.
The PLAGL1 protein helps regulate the cell's process for replicating itself in an organized, step-by-step fashion (cell cycle), and is involved in the self-destruction of cells (apoptosis). It is also important in fetal growth. The PLAGL1 protein helps control another protein called the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1). One of the functions of the PACAP1 protein is to stimulate insulin secretion by beta cells in the pancreas. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.
PLAGL1 is a paternally expressed imprinted gene, which means that normally only the copy of the gene that comes from the father is active. The copy of the gene that comes from the mother is inactivated (silenced) by a mechanism called methylation.
Health Conditions Related to Genetic Changes
6q24-related transient neonatal diabetes mellitus
6q24-related transient neonatal diabetes mellitus, a type of diabetes that occurs in infants, is caused by the overactivity (overexpression) of the PLAGL1 gene. There are three ways that overexpression of the PLAGL1 gene can occur. About 40 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by a genetic change known as paternal uniparental disomy (UPD) of chromosome 6. In paternal UPD, people inherit both copies of a chromosome from their father instead of one copy from each parent. Paternal UPD causes people to have two active copies of paternally expressed imprinted genes, rather than one active copy from the father and one inactive copy from the mother.
Another 40 percent of cases of 6q24-related transient neonatal diabetes mellitus occur when the copy of chromosome 6 that comes from the father has a duplication of genetic material including the PLAGL1 gene.
The third mechanism by which overexpression of the PLAGL1 gene can occur is by impaired silencing of the maternal copy of the gene (maternal hypomethylation). Approximately 20 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by maternal hypomethylation. Some people with this disorder have a genetic change in the maternal copy of the 6q24 region that prevents genes in that region from being silenced. Other affected individuals have a more generalized impairment of gene silencing involving many imprinted regions, called hypomethylation of imprinted loci (HIL). HIL results from mutations in other genes.
It is not well understood how overexpression of the PLAGL1 gene causes 6q24-related transient neonatal diabetes mellitus and why the condition improves after infancy. Researchers suggest that PLAGL1 overexpression may reduce the number of insulin-secreting beta cells or impair their function in affected individuals. Lack of sufficient insulin results in the impaired blood sugar control associated with diabetes mellitus. In individuals with 6q24-related transient neonatal diabetes mellitus, these signs and symptoms are most likely to occur during times of physiologic stress, including the rapid growth of infancy, childhood illnesses, and pregnancy. Because insulin acts as a growth promoter during early development, a shortage of this hormone may account for the slow prenatal growth seen in 6q24-related transient neonatal diabetes mellitus.More About This Health Condition
Excessive silencing (hypermethylation) of the PLAGL1 gene has been identified in various cancerous tumors, including ovarian cancer and cancers of immune system cells (lymphomas). PLAGL1 gene hypermethylation results in decreased production of the PLAGL1 protein. A shortage of the PLAGL1 protein likely impairs its role in regulating the cell cycle and interferes with apoptosis. As a result, cells may grow and divide too quickly or in an uncontrolled way, leading to cancer.
Other Names for This Gene
- lost on transformation 1
- PLAG-like 1
- pleiomorphic adenoma gene-like 1
- pleiomorphic adenoma-like protein 1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Abdollahi A. LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions. J Cell Physiol. 2007 Jan;210(1):16-25. doi: 10.1002/jcp.20835. Citation on PubMed
- Diatloff-Zito C, Nicole A, Marcelin G, Labit H, Marquis E, Bellanne-Chantelot C, Robert JJ. Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical region. J Med Genet. 2007 Jan;44(1):31-7. doi: 10.1136/jmg.2006.044404. Epub 2006 Sep 13. Citation on PubMed or Free article on PubMed Central
- Docherty LE, Poole RL, Mattocks CJ, Lehmann A, Temple IK, Mackay DJ. Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes. Diabetologia. 2010 Nov;53(11):2347-51. doi: 10.1007/s00125-010-1853-2. Epub 2010 Jul 30. Citation on PubMed
- Kamikihara T, Arima T, Kato K, Matsuda T, Kato H, Douchi T, Nagata Y, Nakao M, Wake N. Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer. Int J Cancer. 2005 Jul 10;115(5):690-700. doi: 10.1002/ijc.20971. Citation on PubMed
- Mackay DJ, Temple IK. Transient neonatal diabetes mellitus type 1. Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):335-42. doi: 10.1002/ajmg.c.30272. Citation on PubMed
- Temple IK, Shield JP. 6q24 transient neonatal diabetes. Rev Endocr Metab Disord. 2010 Sep;11(3):199-204. doi: 10.1007/s11154-010-9150-4. Citation on PubMed
- Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet. 2002 Dec;39(12):872-5. doi: 10.1136/jmg.39.12.872. Citation on PubMed or Free article on PubMed Central
- Temple IK. Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith-Wiedemann syndrome. Endocr Dev. 2007;12:113-123. doi: 10.1159/000109638. Citation on PubMed
- Valleley EM, Cordery SF, Bonthron DT. Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. Hum Mol Genet. 2007 Apr 15;16(8):972-81. doi: 10.1093/hmg/ddm041. Epub 2007 Mar 6. Citation on PubMed
- Valleley EM, Cordery SF, Carr IM, MacLennan KA, Bonthron DT. Loss of expression of ZAC/PLAGL1 in diffuse large B-cell lymphoma is independent of promoter hypermethylation. Genes Chromosomes Cancer. 2010 May;49(5):480-6. doi: 10.1002/gcc.20758. Citation on PubMed
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