Multiple endocrine neoplasia, type 1, 2 and 4 (Multiple endocrine neoplasia types 1, 2 and 4) - Genes MEN1, RET and CDKN1B.
Multiple endocrine neoplasia is a group of disorders that affect the endocrine system. This disease usually involves neoplasms in at least two endocrine glands. Tumors can also develop in other organs and tissues. These growths can be benign or malignant. If the tumors become cancerous, the condition can be life threatening.
The main forms of multiple endocrine neoplasia type are called 1, type 2 and type 4. These types differ in genes involved, the types of encoded hormones, and signs and symptoms. Many different types of tumors are associated with multiple endocrine neoplasia. Type 1, frequently it involves tumors of the parathyroid glands, the pituitary gland and pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is hyperparathyroidism, which alters the normal balance of calcium in the blood, which can cause kidney stones, bone loss, nausea and vomiting, hypertension, weakness and fatigue. For its part, the most common sign of multiple endocrine neoplasia type 2 is medullary thyroid carcinoma. Some people with type 2 also develop a pheochromocytoma, a tumor of the adrenal gland which can cause very high blood pressure. In turn, multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and thyroid medullary carcinoma familiar (MCTF). These subtypes differ in their signs and symptoms and the risk for developing specific tumors characteristic. For example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the unique feature of MCTF. Signs and symptoms of multiple endocrine neoplasia type 2 are relatively constant within the same family. Type 4 disease and appears to have signs similar to those of type 1, although it is caused by mutations in a gene other symptoms. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.
This disease is due to mutations in the MEN1, RET and CDKN1B genes.
MEN1 gene, located on the long arm of chromosome 11 (11q13), encodes a protein called menin, which acts as a tumor suppressor. Although the exact role of menin is unknown, it is likely to be involved in cellular functions such as copying and repairing DNA and regulate the activity of other genes. When mutations inactivating both copies of the MEN1 gene, the protein is no longer available to control growth and cell division. The loss of functional menin allows cells divide too often, resulting in formation of characteristic tumors multiple endocrine neoplasia type 1. There are more than 1,300 mutations in the MEN1 gene in individuals with multiple endocrine neoplasia type 1. most mutations result encoding an abnormally short and inactive version menin or an unstable protein which is rapidly decomposed. As a result of these mutations, a copy of the MEN1 gene in each cell does not encode functional protein. If the second copy of the MEN1 gene is also alters the cell does not encode functional menin. For unknown reasons, a second mutation occurs more frequently in cells of the endocrine glands. No menina, these cells can divide too often and form tumors. Though menin appears to be necessary to prevent tumor formation, it is not clear how the lack of this protein leads to specific tumors characteristic of multiple endocrine neoplasia type 1.
The RET gene, located on the long arm of chromosome 10 (10q11.2), encodes a protein involved in signaling within cells. This protein appears to be essential for normal development of various types of nerve cells, including neurons and enteric autonomic nervous system. The RET protein is also required for normal kidney development and spermatogenesis. Additionally, the protein interacts with specific factors outside the cell and receives signals that help the cell to respond to its environment. When molecules that stimulate growth and development bind to the protein, a complex cascade of chemical reactions triggered within the cell. These reactions cause the cell to respond to its environment, for example, dividing or maturing. Have identified more than 25 mutations in the RET gene in people with multiple endocrine neoplasia type 2. Most mutations change amino acids in the protein. A mutation replaces the amino acid arginine by the amino acid cysteine at position 634 (Cys634Arg or C634R). Over 90% of cases of type 2B are caused by a mutation that replaces the amino acid methionine threonine by amino acid position 918 (Met918Thr or M918T). Mutations responsible for multiple endocrine neoplasia type 2 give rise to a protein overactive RET probably causes the cells to grow and divide abnormally, which can lead to tumor formation in the endocrine system and other tissues .
The CDKN1B gene, located on the short arm of chromosome 12 (12p13.1-p12), p27 protein encoding. This protein is found in cells and tissues throughout the body. Like menin protein, p27 protein is a tumor suppressor that helps control cell growth and division. Studies suggest that p27 protein is also involved in the control of cell differentiation. They have identified at least eight mutations in the gene CDKN1B in people with multiple endocrine neoplasia type 4. Mutations in the gene coded CDKN1B reduce the amount of functional p27, which allows cells to grow and divide without control. This unregulated cell division can lead to the development of tumors in endocrine glands , and other tissues.
Most cases of multiple endocrine neoplasia type 1 are considered to have an autosomal dominant inheritance. People with this disorder are born with a mutated copy of the MEN1 gene in each cell. In most cases, the altered gene is inherited from one of the affected parents. The remaining cases are due to new mutations in the MEN1 gene and occur in people with no history of disease in your family. Unlike most other common autosomal dominant disorders in which an altered copy of a gene in each cell is sufficient to express the disease, in the case of multiple endocrine neoplasia type 1, the two copies of the MEN1 gene should be altered to trigger tumor formation. A mutation in the second gene copy MEN1 occurs in a small number of cells during the life of a person. Almost all people born with a mutation in the gene MEN1 acquire a second mutation in certain cells, which can then be divided in a manner causing unregulated tumors. Meanwhile, multiple endocrine neoplasia type 2 and type 4 also inherited in an autosomal dominant pattern. In these cases, a single copy of the mutated gene is sufficient to lead to alteration. People usually inherit the RET gene or altered gene CDKN1B a parent with the disease. However, some cases are due to new mutations in the gene and occur in people with no other affected family members.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with multiple endocrine neoplasia, by complete PCR amplification of the exons of the MEN1, RET and CDKN1B, 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).