RET

The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the portion of the nervous system that controls involuntary body functions such as heart rate (the autonomic nervous system). The RET protein is also necessary for normal kidney development and the production of sperm (spermatogenesis).

The RET protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment. When growth factors attach to the RET protein, it triggers a complex cascade of chemical reactions inside the cell. These reactions instruct the cell to undergo certain changes, such as dividing or maturing to take on specialized functions.

multiple endocrine neoplasia - caused by mutations in the RET gene

More than 25 mutations in the RET gene are known to cause multiple endocrine neoplasia type 2. Most of these mutations change single protein building blocks (amino acids) in the RET protein. The most common mutation responsible for multiple endocrine neoplasia type 2A substitutes the amino acid arginine for the amino acid cysteine at position 634 (written as Cys634Arg or C634R). Another mutation causes more than 90 percent of cases of multiple endocrine neoplasia type 2B; this change replaces the amino acid methionine with the amino acid threonine at position 918 (written as Met918Thr or M918T). Several amino acid substitutions can cause familial medullary thyroid carcinoma, the third subtype of multiple endocrine neoplasia type 2.

Mutations responsible for multiple endocrine neoplasia type 2 result in an overactive RET protein that can transmit signals without first attaching to growth factors outside the cell. The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine system and other tissues.

other disorders - caused by mutations in the RET gene

Mutations in the RET gene are one cause of Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. These genetic changes result in a nonfunctional version of the RET protein that cannot interact with growth factors or transmit signals within cells. Without RET signaling, enteric nerves do not develop properly. Because these nerves control contractions that move stool through the intestine, their absence leads to the intestinal problems characteristic of Hirschsprung disease. The inactivating RET mutations that cause Hirschsprung disease are very different from the overactivating mutations that cause multiple endocrine neoplasia type 2; these two disorders rarely occur in the same individual.

other cancers - associated with the RET gene

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic changes in the RET gene have been identified in several nonhereditary (sporadic) cancers. Chromosomal rearrangements involving the RET gene are one of the most common causes of a sporadic form of thyroid cancer called papillary thyroid carcinoma (also known as RET/PTC). Another type of thyroid cancer, medullary thyroid carcinoma, also can be caused by somatic mutations in the RET gene. In addition, RET mutations have been identified in a small percentage of pheochromocytomas, which are tumors of the adrenal glands that can cause dangerously high blood pressure