Deficiency family glucocorticoids (glucocorticoid deficiency Familial) - Genes MC2R, MRAP, and NNT.
Glucocorticoid deficiency family is a condition that occurs when the adrenal glands do not produce glucocorticoid. These hormones, including cortisol and corticosterone, involved in immune system function, play a role in maintaining normal levels of blood glucose, help activating signaling of nerve cells in the brain, and serve for many other purposes in the body.
Adrenal insufficiency leads to the signs and symptoms of glucocorticoid deficiency family. Often these signs and symptoms begin in infancy or early childhood and may include hypoglycemia and growth retardation. If left untreated, hypoglycemia can lead to seizures, learning disabilities and other neurological problems. Untreated hypoglycemia for prolonged periods can cause neurological damage and death. Other features of the disease may include recurrent infections and hyperpigmentation. There are several types of deficiency familiar glucocorticoids, which are distinguished by their genetic cause.
Most cases of family glucocorticoid deficiency are due to mutations in MC2R, MRAP and NNT genes. Mutations in other genes, some known and some unidentified, can also lead to disease.
The MC2R gene, located on the short arm of chromosome 18 (18p11.2), encodes a protein called receptor adrenocorticotropic hormone (ACTH), which is mainly found in the adrenal glands. The ACTH receptor located on the cell membrane where it binds to hormone ACTH. This hormone is released by the pituitary gland in the brain stem. ACTH binding to its receptor causes the adrenal glands to glucocorticoids. In addition, the ACTH receptor probably plays a role in the development of the adrenal glands before birth. They have identified more than 40 mutations in the gene responsible for MC2R family glucocorticoid deficiency. Mutations in this gene represent approximately 25% of cases of this disease. Most of these mutations change the amino acids in the ACTH receptor. As a result, the receiver can not be transported to the cell membrane or attached to ACTH. Without the receptor binding ACTH its hormone, no signal to activate the adrenal glands to produce glucocorticoids. Deficiency of these hormones affect the regulation of blood glucose, immune system function and other cellular functions, leading to signs and symptoms of deficiency glucocorticoid family.
MRAP gene, located on the long arm of chromosome 21 (21q22.1), encoding the receptor accessory protein 2 melanocortin (MRAP). This protein carries another protein, termed melanocortin receptor 2, or the receptor of adrenocorticotropic hormone [ACTH], from inside the cell to the cell surface. Specifically, the MRAP protein carries the ACTH receptor from the endoplasmic reticulum (ER), which is involved in the processing and transport of proteins to the cell membrane so that the receiver can operate. The MRAP protein is also required to activate the ACTH receptor. In the cell membrane, aggregates activated receptors (ACTH) bind to ACTH, which triggers the production of glucocorticoids. They have identified at least 13 mutations in the gene MRAP generating deficiency glucocorticoid family. MRAP gene mutations account for approximately 20% of cases of this disease. Most of these mutations lead to encoding a protein that can not interact with the ACTH receptor and therefore is unable to carry out the ER to the cell membrane. Consequently, the ACTH receptor is not on the cell surface where it is needed to bind to ACTH. Without the receptor binding ACTH its hormone, no signal to activate the adrenal glands to produce glucocorticoids. The lack of these hormones affect the regulation of blood sugar, the function of the immune system and other cell functions, leading to the signs and symptoms of glucocorticoid deficiency family.
The NNT gene, located on the short arm of chromosome 5 (5p12), encoding the nucleotide transhydrogenase enzyme nicotinamide, located in the inner membrane of mitochondria. This enzyme helps produce a substance called NADPH, which is involved in the elimination of reactive oxygen species that can damage DNA membranes, proteins and cells. The nucleotide transhydrogenase enzyme nicotinamide found throughout the body, but is particularly abundant in adrenal glands that produce hormones and thyroid, heart, kidney and adipose tissue. They have identified at least 25 NNT gene mutations leading to deficiency of glucocorticoids family. NNT gene mutations account for approximately 10% of cases of this disease. Most mutations change the amino acid in nicotinamide nucleotide transhydrogenase enzyme, altering the ability of the enzyme to produce NADPH, which leads to increased reactive oxygen species in the adrenals. Over time, these toxic molecules can affect the function of cells of the adrenal gland and lead to apoptosis, decreasing production of glucocorticoids. The lack of these hormones affect the regulation of blood sugar, the function of the immune system and other cell functions, leading to the signs and symptoms of glucocorticoid deficiency family.
This disease is inherited in an autosomal recessive pattern, that is, 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 in IVAMI: in IVAMI perform detection of mutations associated with glucocorticoid deficiency family, by complete PCR amplification of the exons of the MC2R, MRAP , and NNT, genes and subsequent sequencing.
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).