STAT3 gain-of-function disease (also called STAT3 GOF disease) is a rare genetic disorder of the immune system. STAT3 GOF disease is named after the gene that causes it, STAT3 (signal transducer and activator of transcription 3), and the effect caused by mutations in STAT3—gain-of-function, meaning that the gene’s protein becomes overactive.

STAT3 GOF disease is an early-onset autoimmune and lymphoproliferative disease. The symptoms of this disease vary and can include swelling of the lymph nodes (lymphadenopathy), reduc tions in the number of blood cells (autoimmune cytopenias), autoimmunity that affects multiple organs and tissues, infections, eczema, and in some cases, short stature. Sarah Flanagan and Mark Russell of University of Exeter Medical School and Joshua Milner of NIAID originally described this condition in 19 patients in 2014 and 2015. Since then, dozens of additional patients have been identified.

STAT3 GOF disease is caused by gain of-function mutations in the STAT3 gene. This gene provides instructions for production of the STAT3 protein, part of the STAT family of proteins. Various mutations have been identified across the length of the STAT3 protein.

STAT proteins play an essential role in chemical signaling pathways within cells. STAT3 is a transcription fac tor, a type of protein that regulates when other genes are turned on. Once activated, STAT3 moves into the nucleus of the cell and binds to specific areas of DNA. By binding to regula tory DNA regions near genes, STAT3 controls the activity of a variety of genes. It is necessary for many cellular processes, including cell proliferation, inflammation, differentiation, and cell survival.

Normal Function

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 turned on (activated) by certain chemical signals, they move into the cell's nucleus and attach (bind) to particular areas of DNA. The STAT proteins bind to regulatory regions near genes, which allows the proteins to control whether these genes are turned on or off. STAT proteins are called transcription factors on the basis of this action.

Through its regulation of gene activity, the STAT3 protein is involved in many cellular functions. It helps control cell growth and division (proliferation), cell movement (migration), 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, and it plays a role in cellular processes that promote allergic reactions.

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.

Health Conditions Related to Genetic Changes

Autosomal dominant hyper-IgE syndrome

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, teeth, and blood vessels. The condition is characterized by high levels of an immune system protein called immunoglobulin E (IgE), which is involved in allergic reactions. Most of the mutations involved in this condition change single amino acids in the STAT3 protein.

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. Most of these mutations have a dominant-negative effect, which means that the altered protein produced from one copy of the STAT3 gene interferes with the function of the normal protein produced from the other copy of the gene.

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.

A shortage of functioning STAT3 protein prevents cells from reacting to signals that trigger allergic reactions, which explains why people with AD-HIES do not have an increased risk of allergies, despite having high levels of IgE. It is unclear why levels of this protein are elevated in affected individuals.

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, but it is unclear what causes blood vessel abnormalities in AD-HIES.

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

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Shingles

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Autoimmune disorders

At least 20 STAT3 gene mutations have been found to cause an autoimmune disorder that affects many body systems. Autoimmune disorders are a group of immune system abnormalities in which the immune system malfunctions and attacks the body's own cells and tissues.

In people with these STAT3 gene mutations, autoimmunity typically begins in infancy or early childhood and involves more than one body system. In these individuals, signs and symptoms commonly result 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 these conditions 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. Abnormal STAT3 activity prevents normal control of the immune system, leading to autoimmunity.

Cancers

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.

Individuals with LGL 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 the autoimmunity (described above), LGL-associated STAT3 gene mutations are not inherited and are found only in the abnormal lymphocytes. (Such mutations are 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.

Other Names for This Gene

• acute-phase response factor
• APRF
• APRF Transcription Factor
• DNA-binding protein APRF
• FLJ20882
• hypothetical protein MGC16063
• IL6-Response Factor
• LIF(leukemia inhibitory factor)-Response Factor
• LIF-Response Factor
• signal transducer and activator of transcription 3 (acute-phase response factor)
• STAT3_HUMAN

Genomic Location

STAT3 GOF disease is inherited in an autosomal dominant manner, which means that a person needs an abnormal gene from only one parent to have the disease. The abnor mal STAT3 gene dominates the normal STAT3 gene from the other parent. Dominant inheritance also means that most families with STAT3 GOF disease have affected rela tives in each generation on the side of the family with the mutation. However, researchers have found that, in some families, relatives carrying a STAT3 mutation do not have symptoms of the disease. This is called incomplete penetrance.

Unlike mutations that run in a family, some STAT3 mutations occur as a result of a mutation in the egg or sperm of one of the parents or in the fertilized egg itself. These are called de novo, which means “new” mutations. In these cases, the patient does not have a family history of similar symptoms. De novo mutations can be passed on to children.

Children of a parent who carries a STAT3 mutation have a 50 percent chance of inheriting the mutation. This means that, within a given family, each child’s risk of inheriting the mutated gene is independent of whether or not siblings have the mutation. For example, if the first three children in a family have the mutation, the fourth child has the same 50 percent risk of inheriting the mutation. Children who do not inherit the abnormal gene will not develop STAT3 GOF disease or pass on the mutation.

Clinically, STAT3 GOF disease is diverse. It is characterized by a buildup of immune cells called lymphocytes (lymphoproliferation) and early-onset autoimmunity affecting multiple organs and tissues. Exactly when, where, and to what extent these problems will develop in any one person cannot be predicted.

Lymphoproliferation: The main signs or symptoms of lymphoproliferation are lymphadenopathy (enlarged or swollen lymph nodes that wax and wane over time) and/or splenomegaly (an enlarged spleen) and sometimes hepatomegaly (an enlarged liver).

Autoimmunity: Hematologic autoimmunity is the most common type of autoimmunity in STAT3 GOF disease. This includes autoimmune hemolytic anemia (attacks against red blood cells), neutropenia (attacks against white blood cells), and/or thrombocytopenia (attacks against platelets). Autoimmunity also can develop against other organs and tissues. Examples of such autoimmune problems include arthritis (attacks against joints), lung disease (attacks against lungs), hepatitis (attacks against liver), eczema (attacks against skin), alopecia (attacks against hair follicles), type 1 diabetes (attacks against part of the pancreas), and/or scleroderma (attacks against skin and connective tissue).

Some patients also have recurrent, severe infec tions and fungal infections with low antibody levels (hypogammaglobulinemia). Some patients have short stature, with some exhibiting profound growth failure. In rare cases, patients with STAT3 GOF develop cancers, such as lymphoma.

Notably, the clinical symptoms of STAT3 GOF patients differ distinctly from those associated with STAT3 loss-of-function mutations. STAT3 lossof-function mutations are responsible for hyperimmunoglobulin E syndrome, also called Job’s syndrome, which is characterized by recurrent skin infections, unusual eczema-like skin rashes, and susceptibility to severe lung infections.

STAT3 GOF patients have moderately low levels of T cells, hypogammaglobulinemia, and elevated levels of immune cells called double negative CD4/CD8 T cells. More studies are required to better under stand the connection between these laboratory findings and the type and severity of clinical symptoms.

Treatment is based on a person’s clinical condition and may include standard therapies for autoim mune problems. In one reported case, a patient with severe autoimmune hemolytic anemia responded well to the drug rituximab. In another case, use of the drug tocilizumab resulted in a dramatic improvement in one patient’s arthritis. Some patients with short stature have responded well to growth hormone treatment. Bone marrow transplant is a possible treatment for this condition and has been used with mixed results in a small number of patients with severe disease.

More research with larger numbers of patients is required to further assess these therapeutic approaches.

Living with STAT3 GOF disease can be difficult not only for the person who has it but also for their family members. It is important for families to talk openly about STAT3 GOF disease and about how the family is dealing with it so misconceptions can be corrected and children can learn to cope with their reactions. Some children with STAT3 GOF disease have to work hard to develop their self-confidence and sense of security. Everyone needs to be reminded that they have many positive characteristics, especially when their appearance attracts attention (for example, due to large lymph nodes).

Some children who have siblings with STAT3 GOF disease worry about their brother or sister being in pain or dying from the disease. Some think that they may develop symptoms because they look or act like a sibling who has the disease or that the disease is contagious. Some children struggle with how much time their parents spend with their sick sibling. Many families benefit from meeting or talking to other families affected by the same rare disease. Patient organizations such as the Immune Deficiency Foundation (www.primaryimmune.org) also are great resources for providing useful information and support. Counseling also can help families cope with the challenges of living with a chronic condition.

At the same time, many families say that STAT3 GOF disease has brought them closer together. Family members learn about controllable and uncontrollable aspects of life. Although certain aspects of the disorder cannot be controlled, how a family responds to the stress of any illness is controllable and an important aspect of managing STAT3 GOF disease. Children also learn who they can turn to for support and how to solve problems. Acknowledging both the challenges and opportunities that STAT3 GOF disease presents helps children develop resilience.