Transient neonatal diabetes mellitus related 6q24 (6q24-related transient neonatal diabetes mellitus) - Genes HYMAI, PLAGL1, ZFP57 and chromosome 6

           

Neonatal diabetes mellitus related transient 6q24 is a type of diabetes which occurs in newborns. Signs and symptoms associated with this disease include severe intrauterine growth retardation and hyperglycemia and dehydration usually from the first week of life. Signs and symptoms of this form of diabetes are transient, and gradually decrease over time and usually disappear between the ages of 3 and 18 months. However, diabetes can happen again especially during childhood diseases or pregnancy. About half of individuals with diabetes mellitus Transient neonatal 6q24 associated with permanent diabetes mellitus may develop later in life. Other features of the condition that occur in some affected individuals include macroglossia, umbilical hernia, malformations of the brain, heart or kidneys, hypotonia, deafness and developmental delay.

This process is due to overexpression of certain genes in a region of the long arm of chromosome 6 known 6q24. People inherit two copies of their genes, one from each parent. Usually, the two copies of each gene is activated in cells. However, in some cases only one of the two copies is normally activated. The copy is activated depends on the source array: some genes normally activated only when inherited from the father; others are active only when inherited from the mother. This phenomenon is known as genomic imprinting. 6q24 region includes gene expression paternally, which means that usually only the copy of each gene from the father is active. Copy of each gene comes from the mother is inactivated by a mechanism called methylation. It is believed that hyperactivity of one of the paternally expressed imprinted genes in this region, PLAGL1 (PLAG1 like zinc finger 1), cause neonatal diabetes mellitus related transient 6q24. Other imprinted genes expressed from the paternal copy in the region, some of which have not been identified, also may be involved in the development of this disease.

There are three ways in which over - expression of imprinted genes can occur in the region 6q24. About 40% of cases of neonatal diabetes mellitus associated with transient 6q24 are due to a genetic change known as paternal uniparental disomy (UPD) of chromosome 6. The UPD, people inherit two copies of the affected chromosome from their father in instead of one copy from each parent, which causes people to have two active copies of imprinted genes expressed from the father, rather than an active copy of the father and an inactive copy of the mother. Another 40% of cases of transient neonatal diabetes mellitus associated with 6q24 occur when the copy of chromosome 6 inherited from the father has a duplication of genetic material including imprinted genes expressed from the paternal route in the region 6q24. The third mechanism by which can produce the overexpression of genes in the 6q24 region is altered silencing maternal copy genes (maternal hypomethylation). Approximately 20% of cases of diabetes mellitus associated with transient neonatal 6q24 are due to maternal hypomethylation.

Some people with this disease have a genetic change in the maternal copy of the 6q24 region that prevents genes in the region are silenced. Other affected individuals have an increased overall deterioration of gene silencing involving many printed regions, called hypomethylation printed loci (HIL). About half of the cases, the HIL is due to mutations in the gene ZFP57 (zinc finger protein). The protein encoded from this gene is important in the establishment and maintenance of gene silencing. HIL other causes are unknown. Because the HIL may cause overexpression of many genes, this mechanism can respond to additional health problems that occur in some people with diabetes mellitus associated with transient neonatal 6q24. It is not well understood how overexpression of PLAGL1 and other genes in the region 6q24 lead to the development of diabetes mellitus Transient neonatal 6q24 related and why the disease improves after childhood.

The PLAGL1 (PLAGL1 like zinc finger 1) gene, located on the long arm of chromosome 6 (6q24-q25), encodes a member of the family of zinc finger proteins. The PLAGL1 protein helps regulate cellular process to divide an organized manner, and is involved in apoptosis. It is also important in embryonic growth. PLAGL1 protein helps control another protein called cyclase activating polypeptide pituitary adenylate type I (PACAP1). One function of the protein is PACAP1 stimulate insulin secretion by the beta cells in the pancreas. It is not well understood how PLAGL1 overexpression of the gene results in diabetes mellitus associated with transient neonatal 6q24 and why the disease improves after childhood. It is believed that overexpression of PLAGL1 can reduce the number of insulin - secreting beta cells or impair their function in affected individuals. In affected individuals, it is more likely that the signs and symptoms of the disease manifest themselves during times of physiological stress, including the rapid growth of childhood, childhood diseases and pregnancy. Because insulin acts as a growth promoter in early development, deficiency of this hormone may explain the slow prenatal growth.

The protein encoded from ZFP57 (ZFP57 zinc finger protein) gene, located on the short arm of chromosome 6 (6p22.1) is a member of the family of zinc finger proteins that are involved in many cellular functions. These proteins each contain one or more zinc finger domains. These regions include a specific amino acid pattern and one or more zinc ions. The zinc finger proteins are transcription factors. Some zinc finger proteins can also bind to other molecules, including RNA and proteins. The ZFP57 protein is involved in the regulation of other genes by methylation. Methylation is important in many cellular functions. These include determination of gene silencing, regulation of reactions involving proteins and lipids, and control the processing of neurotransmitters. Mutations in the gene ZFP57 are responsible for about 10% of cases of diabetes mellitus related transient neonatal 6q24. These mutations hypomethylation printed loci (HIL) which affects many printed regions including the print region 6q24. Hyperactivity resulting from the genes in the region 6q24 that are involved in regulating insulin secretion and apoptosis, can reduce the number of insulin - secreting beta cells or impair their function in affected individuals.

It is believed that HYMAI gene (hydatidiform mole and imprinted associated -non-protein coding), located on the long arm of chromosome 6 (6q24.2), is another responsible for transient neonatal diabetes mellitus (TNDM). This gene encodes a protein antisense transcript expressed only the paternal allele.

Most cases of diabetes mellitus associated with transient neonatal 6q24 not inherited, particularly those due to a paternal UPD. In these cases, genetic changes occur as random events during the formation of reproductive cells or early embryonic development, so affected individuals often have no history of the disease in his family. Sometimes the genetic change responsible for the disease may be inherited. For example, a duplication of genetic material on the paternal chromosome 6 can be transmitted from one generation to the next. When diabetes transient neonatal mellitus related 6q24 is due to mutations in the ZFP57 gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with diabetes mellitus transient neonatal 6q24 related by the complete PCR amplification of the exons of HYMAI, PLAGL1, ZFP57, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).