6q24-related transient neonatal diabetes mellitus is a type of diabetes that occurs in infants. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.

People with 6q24-related transient neonatal diabetes mellitus experience very slow growth before birth (severe intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration), usually beginning in the first week of life. Signs and symptoms of this form of diabetes are transient, which means that they gradually lessen over time and generally disappear between the ages of 3 months and 18 months. Diabetes may recur, however, especially during childhood illnesses or pregnancy. Up to half of individuals with 6q24-related transient neonatal diabetes mellitus develop permanent diabetes mellitus later in life.

Other features of 6q24-related transient neonatal diabetes mellitus that occur in some affected individuals include an unusually large tongue (macroglossia); a soft out-pouching around the belly-button (an umbilical hernia); malformations of the brain, heart, or kidneys; weak muscle tone (hypotonia); deafness; and developmental delay.

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.

Normal Function

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 glucose 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.

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.

Other Names for This Gene

• lost on transformation 1
• LOT-1
• LOT1
• MGC126275
• MGC126276
• PLAG-like 1
• PLAL1_HUMAN
• pleiomorphic adenoma gene-like 1
• pleiomorphic adenoma-like protein 1
• ZAC
• ZAC1

Genomic Location

Normal Function

The protein produced from the ZFP57 gene is a member of a family called zinc finger proteins, which are involved in many cellular functions. Zinc finger proteins each contain one or more short regions called zinc finger domains. These regions 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, these proteins 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 ZFP57 protein is involved in the regulation of other genes by the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms (methylation). Methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed (gene silencing), regulating reactions involving proteins and lipids, and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters).

Health Conditions Related to Genetic Changes

6q24-related transient neonatal diabetes mellitus

Mutations in the ZFP57 gene cause about 10 percent of cases of 6q24-related transient neonatal diabetes mellitus, a type of diabetes that occurs in infants. This disorder results from 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 methylation.

ZFP57 gene mutations cause a generalized impairment of gene silencing called hypomethylation of imprinted loci (HIL), which affects many imprinted regions including the imprinted region of 6q24. The resulting overactivity of genes in the 6q24 region that are involved with the regulation of insulin secretion and the self-destruction of cells (apoptosis) may reduce the number of insulin-secreting beta cells or impair their function in affected individuals. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. A shortage of insulin results in the impaired blood glucose control associated with diabetes mellitus.

Because HIL resulting from ZFP57 gene mutations can affect expression of many imprinted genes, this mechanism may account for the additional health problems that occur in some people with 6q24-related transient neonatal diabetes mellitus, such as malformations of the brain, heart, or kidneys.

Other Names for This Gene

• bA145L22
• bA145L22.2
• C6orf40
• TNDM1
• zfp-57
• ZFP57_HUMAN
• zinc finger protein 57 homolog
• zinc finger protein 57 homolog (mouse)
• zinc finger protein 698
• ZNF698

Genomic Location

Most cases of 6q24-related transient neonatal diabetes mellitus are not inherited, particularly those caused by paternal uniparental disomy. In these cases, genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Sometimes, the genetic change responsible for 6q24-related transient neonatal diabetes mellitus is inherited. For example, a duplication of genetic material on the paternal chromosome 6 can be passed from one generation to the next.

When 6q24-related transient neonatal diabetes mellitus is caused by ZFP57 gene mutations, it is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Between 1 in 215,000 and 1 in 400,000 babies are born with diabetes mellitus. In about half of these babies, the diabetes is transient. Researchers estimate that approximately 70 percent of transient diabetes in newborns is caused by 6q24-related transient neonatal diabetes mellitus.