STAT3 gene

signal transducer and activator of transcription 3

The STAT3 gene is part of a family known as the STAT genes. These genes provide instructions for making proteins that are part of essential chemical signaling pathways within cells. When STAT proteins are activated by certain chemical signals, they move into the nucleus and attach (bind) to specific areas of DNA. By binding to regulatory regions near genes, STAT proteins can regulate whether these genes are turned on or off. STAT proteins are called transcription factors on the basis of this action.

The STAT3 protein is involved in many cellular functions. It regulates genes that are involved in cell growth and division, cell movement, and the self-destruction of cells (apoptosis). The STAT3 protein is active in tissues throughout the body. It plays an important role in the development and function of several body systems and is essential for life. In the immune system, the STAT3 protein transmits signals for the maturation of immune system cells, especially T cells and B cells. These cells help control the body's response to foreign invaders such as bacteria and fungi. In addition, the protein is involved in the regulation of inflammation, which is one way the immune system responds to infection or injury. In the skeletal system, the STAT3 protein is involved in the formation of specialized cells that build and break down bone tissue. These cells are necessary for the normal development and maintenance of bones.

More than 100 germline mutations in the STAT3 gene have been identified in people with autosomal dominant hyper-IgE syndrome (AD-HIES), a disorder of the immune system that leads to recurrent skin and lung infections as well as abnormalities of the bones and teeth. Most of the mutations involved in this condition change single amino acids in the STAT3 protein. These mutations occur in regions of the protein that are critical for its activation or its ability to bind to DNA.

Changes in the STAT3 gene that cause AD-HIES alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. Because the mutations lead to impairment of the protein's normal function, they are called "loss-of-function" mutations. The lack of STAT3's signaling function disrupts the normal maturation of T cells (specifically a subset known as Th17 cells) and other immune system cells. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections, particularly bacterial and fungal infections affecting the lungs and skin. Additionally, the role of STAT3 protein in the formation and maintenance of bone tissue may help explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of this condition.

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At least 20 STAT3 gene mutations have been found to cause a type of immune system abnormality known as an autoimmune disorder, in which the immune system malfunctions and attacks the body's own cells and tissues. In people with these mutations, autoimmunity typically begins in infancy or early childhood and involves more than one body system. Autoimmune disease in these individuals often results from immune system attacks on insulin producing cells in the pancreas (type 1 diabetes), red blood cells (autoimmune hemolytic anemia), platelets (autoimmune thrombocytopenia), or tissues in the digestive tract (autoimmune enteropathy). The mutations involved in this condition are typically inherited and are found in every cell of the body (known as germline mutations). They change single protein building blocks (amino acids) in the STAT3 protein, resulting in an altered protein that is abnormally active. Due to this effect, the mutations are classified as "gain-of-function."

Normally, the STAT3 protein is switched on and off in response to signals that control cell growth and development. A continuously active version of this protein relays messages to the nucleus even in the absence of these chemical signals. It is unclear how overactive STAT3 leads to dysregulation of the immune system and autoimmunity.

STAT3 gene mutations are found in approximately one-third of cases of a blood cancer called large granular lymphocytic leukemia (LGL), which is characterized by the accumulation of white blood cells (lymphocytes) that are abnormally large and contain structures called granules. Affected individuals may also have an autoimmune disorder, primarily rheumatoid arthritis or autoimmune hemolytic anemia, and other blood cell abnormalities, such as pure red cell aplasia. There are two forms of the condition, based on the type of white blood cell involved: T-cell large granular lymphocytic leukemia (T-LGL) and chronic lymphoproliferative disorders of NK cells (CLPD-NKs). Both forms have the same signs and symptoms.

Unlike mutations that cause autoimmunity (described above), LGL-associated STAT3 gene mutations are not inherited and are found only in the abnormal cells (known as somatic mutations). The mutations involved in LGL are classified as "gain-of-function," leading to an overactive STAT3 protein. Researchers believe that the overactive STAT3 protein instructs cells to continue growing and dividing, and prevents damaged cells from self-destructing (undergoing apoptosis). Excess STAT3 protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide uncontrollably.

Cytogenetic Location: 17q21.2, which is the long (q) arm of chromosome 17 at position 21.2

Molecular Location: base pairs 42,313,324 to 42,388,505 on chromosome 17 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: 17q21.2, which is the long (q) arm of chromosome 17 at position 21.2
  • acute-phase response factor
  • APRF
  • APRF Transcription Factor
  • DNA-binding protein APRF
  • FLJ20882
  • hypothetical protein MGC16063
  • IL6-Response Factor
  • LIF-Response Factor
  • LIF(leukemia inhibitory factor)-Response Factor
  • signal transducer and activator of transcription 3 (acute-phase response factor)
  • STAT3_HUMAN