2.1. 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.

2.2. Cancers

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.