6q24-related transient neonatal diabetes mellitus is caused by the overactivity (overexpression) of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. People inherit two copies of their genes, one from their mother and one from their father. Usually both copies of each gene are active, or "turned on," in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person's father; others are active only when inherited from a person's mother. This phenomenon is known as genomic imprinting.  The 6q24 region includes paternally expressed imprinted genes, which means that normally only the copy of each gene that comes from the father is active. The copy of each gene that comes from the mother is inactivated (silenced) by a mechanism called methylation.  Overactivity of one of the paternally expressed imprinted genes in this region, PLAGL1, is believed to cause 6q24-related transient neonatal diabetes mellitus. Other paternally expressed imprinted genes in the region, some of which have not been identified, may also be involved in this disorder.  There are three ways that overexpression of imprinted genes in the 6q24 region 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 the affected 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 paternally expressed imprinted genes in the 6q24 region.  The third mechanism by which overexpression of genes in the 6q24 region can occur is by impaired silencing of the maternal copy of the genes (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).  About half the time, HIL is caused by mutations in the ZFP57 gene. Studies indicate that the protein produced from this gene is important in establishing and maintaining gene silencing. The other causes of HIL are unknown. Because HIL can cause overexpression of many genes, this mechanism may account for the additional health problems that occur in some people with 6q24-related transient neonatal diabetes mellitus.  It is not well understood how overexpression of PLAGL1 and other genes in the 6q24 region causes 6q24-related transient neonatal diabetes mellitus and why the condition improves after infancy. The protein produced from the PLAGL1 gene helps control another protein called the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1), and one of the functions of this protein is to stimulate insulin secretion by beta cells in the pancreas. In addition, overexpression of the PLAGL1 protein has been shown to stop the cycle of cell division and lead to the self-destruction of cells (apoptosis). Researchers suggest that PLAGL1 gene overexpression may reduce the number of insulin-secreting beta cells or impair their function in affected individuals.  Lack of sufficient insulin results in the signs and symptoms of 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 intrauterine growth retardation seen in 6q24-related transient neonatal diabetes mellitus.