KRAS

The KRAS gene provides instructions for making a protein called K-Ras that is involved primarily in regulating cell division. As part of a signaling pathway known as the RAS/MAPK pathway, the protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The K-Ras protein acts like a switch, and it is turned on and off by the GTP and GDP molecules. To transmit signals, the K-Ras protein must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. The proteins produced from these three genes are GTPases. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

cardiofaciocutaneous syndrome - caused by mutations in the KRAS gene

Mutations in the KRAS gene are an uncommon cause of cardiofaciocutaneous syndrome, accounting for fewer than 5 percent of cases. Several mutations in this gene have been identified in people with characteristic features of the disorder, which include heart defects, distinctive facial features, and skin abnormalities. The mutations change single protein building blocks (amino acids) in the K-Ras protein. The altered protein shows increased GTP binding and a decreased ability to convert GTP to GDP. These effects lead to prolonged activation of the K-Ras protein, which alters tightly regulated RAS/MAPK signaling during development. The altered signaling interferes with the development of organs and tissues throughout the body, leading to the varied signs and symptoms of cardiofaciocutaneous syndrome.

Noonan syndrome - caused by mutations in the KRAS gene

Mutations in the KRAS gene have caused a small number of cases of severe or atypical Noonan syndrome, a condition that affects many parts of the body. Intellectual disability is more common in people who have Noonan syndrome with a KRAS gene mutation than in people with Noonan syndrome caused by a mutation in a different gene.

The KRAS gene mutations associated with Noonan syndrome change single amino acids in a critical region of the K-Ras protein. The resulting protein is overactive, with increased GTP-binding and a decreased ability to convert GTP to GDP. The abnormally active protein alters normal RAS/MAPK signaling and disrupts the development of organs and tissues throughout the body. Researchers believe that increased K-Ras activation leading to defective cell movement and differentiation could play a role in the signs and symptoms of Noonan syndrome, including short stature, heart defects, and skeletal abnormalities.

Rarely, people with Noonan syndrome caused by a KRAS gene mutation will also develop juvenile myelomonocytic leukemia, which is a type of blood cancer that typically affects children or adolescents.

cancers - increased risk from variations of the KRAS 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 mutations in the KRAS gene are involved in the development of several types of cancer. These mutations lead to a K-Ras protein that is more strongly overactivated than the mutations that cause cardiofaciocutaneous syndrome and Noonan syndrome. The abnormal K-Ras protein is always active and can direct cells to grow and divide in an uncontrolled way. Studies suggest that KRAS gene mutations are common in pancreatic, lung, and colorectal cancers. Mutations in the KRAS gene have also been found in other types of cancer.

other disorders - caused by mutations in the KRAS gene

KRAS gene mutations also cause a disorder whose major features overlap with those of Noonan syndrome, cardiofaciocutaneous syndrome, and a related disorder called Costello syndrome. This condition has been described as the KRAS mutation-associated phenotype. People with this condition have variable signs and symptoms that include mild to moderate intellectual disability, distinctive facial features, short stature, an unusually large head (macrocephaly), and hair that is sparse and thin.

At least nine mutations in the KRAS gene have been reported in people with this disorder. Each of these mutations changes a single amino acid in the K-Ras protein. These genetic changes abnormally activate the protein, which alters chemical signaling in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of the KRAS mutation-associated phenotype.