HRAS gene

HRas proto-oncogene, GTPase

The HRAS gene provides instructions for making a protein called H-Ras that is involved primarily in regulating cell division. Through a process known as signal transduction, the H-Ras protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow or divide. The H-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The H-Ras protein acts like a switch, and it is turned on and off by GTP and GDP molecules. To transmit signals, the protein must be turned on by attaching (binding) to a molecule of GTP. The H-Ras protein is turned off (inactivated) when it converts GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

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

Somatic HRAS gene mutations that occur in bladder cells have been associated with some cases of bladder cancer. A particular mutation, the Gly12Val mutation that can cause epidermal nevi (described above), has been identified in a significant percentage of bladder tumors. As a result of this genetic change, the altered H-Ras protein becomes continuously active within the cell. The overactive H-Ras protein directs the cell to grow and divide abnormally, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment.

At least 15 mutations in the HRAS gene have been identified in people with Costello syndrome, a rare condition that affects many parts of the body and increases the risk of developing cancerous and noncancerous tumors. The mutations change single protein building blocks (amino acids) in a critical region of the H-Ras protein. The most common mutation accounts for more than 80 percent of all cases of Costello syndrome; it replaces the amino acid glycine with the amino acid serine at protein position 12 (written as Gly12Ser or G12S).

The HRAS gene mutations that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active) in cells throughout the body. Instead of triggering cell growth in response to signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello syndrome (such as intellectual disability, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Mutations in the HRAS gene are involved in the development of abnormal, noncancerous patches of skin called epidermal nevi (singular: nevus). These patches are caused by an overgrowth of cells in the outer layer of skin (the epidermis). HRAS gene mutations have been found in a majority of people with a certain type of epidermal nevus called a nevus sebaceous. This type is classified as an organoid epidermal nevus because it involves cells that make up structures (or organs) in the skin, usually the hair follicles, the sweat glands, or the sebaceous glands (glands in the skin that produce a substance that protects the skin and hair). Additional tumors often develop in the region of the nevus sebaceous. In rare cases, these tumors are cancerous. HRAS gene mutations are less commonly found in keratinocytic epidermal nevi, a type of epidermal nevus that involves a particular type of epidermal cell called a keratinocyte. Keratinocytic epidermal nevi are not typically associated with additional tumors.

Epidermal nevi are caused by gene mutations that are acquired during the early stages of development before birth. The mutations are present only in the cells of the nevus and not the normal skin cells surrounding it. These changes, which are called somatic mutations, are not inherited. The somatic HRAS gene mutations involved in epidermal nevi, change single amino acids in the H-Ras protein. The most common mutation replaces the amino acid glycine with the amino acid valine at protein position 12 (written as Gly12Val or G12V). These mutations lead to production of an H-Ras protein that is always turned on. The affected skin cells grow and divide more than normal cells, resulting in epidermal nevi.

Genetics Home Reference provides information about head and neck squamous cell carcinoma.

Somatic mutations in the HRAS gene are probably involved in the development of several additional types of cancer. These mutations lead to a version of the H-Ras protein that is always active and can direct cells to grow and divide without control. Studies suggest that HRAS gene mutations may be common in thyroid and kidney cancers. Increased activity (expression) of the HRAS gene has also been reported in other types of cancer.

Somatic HRAS gene mutations are also involved in development of Schimmelpenning syndrome, which is a type of epidermal nevus syndrome. Affected individuals have a type of epidermal nevus called nevus sebaceous (described above) in addition to abnormalities of the brain, eyes, or bones. Problems with these other systems can include seizures, intellectual disability, extra or missing pieces of tissue in eye structures (choristomas or colobomas), underdeveloped bones, and a disorder called rickets that leads to softening and weakening of the bones. Schimmelpenning syndrome is caused by the same gene mutations involved in epidermal nevus. It is thought that the additional signs and symptoms occur because the somatic mutation affects other tissues in addition to the skin.

Cytogenetic Location: 11p15.5, which is the short (p) arm of chromosome 11 at position 15.5

Molecular Location: base pairs 532,242 to 535,567 on chromosome 11 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: 11p15.5, which is the short (p) arm of chromosome 11 at position 15.5
  • C-H-RAS
  • Harvey murine sarcoma virus oncogene
  • Harvey rat sarcoma viral oncogene homolog
  • HRAS1
  • Oncogene, G-RAS
  • RASH1
  • RASH_HUMAN
  • Transformation gene: Oncogene HaMSV
  • Transforming protein P21/H-RAS-1 (C-H-RAS)
  • v-Ha-ras Harvey rat sarcoma viral oncogene homolog