PIK3R1 disease is a rare genetic disease of the immune system that was first described in 2013. The disease goes by several names, including activated PI3K syndrome. It is sometimes called PASLI, which stands for PI3K-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency, or APDS2, which stands for - activated PI3K delta syndrome 2. It also is referred to by the affected protein, p85a.

People with PIK3R1 disease have a weakened immune system, which puts them at risk for frequent infections starting in childhood and continuing through adulthood. These include recurrent infections of the upper respiratory tract and lungs. PIK3R1 disease also is characterized by autoimmunity and chronic lymphoproliferation (buildup of unusually high numbers of immune cells). The lympho proliferation can cause swelling of the lymph nodes and spleen and upper respiratory tract lymphoid hyperplasia (proliferation of cells that make up lymphoid tissue). Some people also have smaller stat ure and experience mild developmental delay. Most people with this disease receive immunoglobulin replacement therapy because they have low levels of immunoglobulin-producing B cells. People with PIK3R1 disease also have an increased risk of lymphoma, a type of cancer.

PIK3R1 disease is caused by muta tions in the PIK3R1 gene, specifically mutations that affect a region called exon 11. The PIK3R1 gene produces a protein called p85a. PIK3R1 muta tions affecting exon 11 cause the p85a protein to be shortened, which leads to overactivation of the important PI3K delta signaling pathway in immune cells. This leads to disruptions in the normal development of immune T cells, causing too many naïve T cells to become effector cells. These effector cells undergo a burst of proliferation and then become senescent, which means they stop growing and dividing. This skew toward senescence results in lowered production of B memory cells, increasing a person’s susceptibility to infection (see the Glossary for more information about these cell types). Mutations in related genes, like PIK3CD, cause similar versions of this disease.

Normal Function

The PIK3R1 gene provides instructions for making a part (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The primary function of the subunit is to regulate the enzyme's activity. Several slightly different versions of this regulatory subunit are produced from the PIK3R1 gene; the most abundant of these is called p85 alpha (p85α).

PI3K is a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival.

Studies suggest that PI3K signaling may be involved in how cells regulate several hormones. One of these hormones is insulin, which helps control levels of blood glucose, also called blood sugar. PI3K signaling may also play a role in the maturation of fat cells (adipocytes).

Health Conditions Related to Genetic Changes

Activated PI3K-delta syndrome

Variants (also called mutations) in the PIK3R1 gene have been found to cause an immune disorder called activated PI3K-delta syndrome. PIK3R1 gene variants cause a form of the condition called activated PI3K-delta syndrome type 2. People with activated PI3K-delta syndrome type 2 typically have recurrent bacterial infections of the respiratory tract and chronic viral infections.

PIK3R1 gene variants lead to an altered p85α protein, sometimes causing it to be abnormally short. These variants are classified as gain-of-function variants because a PI3K-delta enzyme that contains the altered subunit is frequently turned on (overactive).

Studies indicate that overactive PI3K-delta signaling alters the growth of certain immune system cells known as B cells and T cells. T cells mature and die too quickly, and B cells are blocked from maturing at an early stage. The immature B cells cannot respond to foreign invaders and likely self-destruct. The lack of B cells and T cells makes it difficult for people with this disorder to fight off bacterial and viral infections. Overactive PI3K-delta signaling can also stimulate the abnormal proliferation of white blood cells in some affected individuals. Activated PI3K-delta syndrome type 2 is also associated with an increased risk of developing a form of blood cell cancer called lymphoma.

Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay

Variants in the PIK3R1 gene have also been reported to cause a condition known as short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay (often called SHORT syndrome). This condition is characterized by signs and symptoms affecting many parts of the body, including the skin, eyes, teeth, and joints.

The most common PIK3R1 gene variant changes a single protein building block (amino acid) in the regulatory subunit of PI3K. Variants in the PIK3R1 gene alter the structure of the subunit, which reduces the ability of PI3K to participate in cell signaling. Because the variants reduce the enzyme's activity, they are described as loss-of-function variants.

Researchers are working to determine how PIK3R1 gene variants lead to the specific features of SHORT syndrome. PI3K's role in insulin activity may be related to insulin resistance and diabetes, which are problems with blood glucose regulation that are found in some people with SHORT syndrome. Abnormal adipocyte maturation might contribute to a lack of fatty tissue under the skin (lipoatrophy), which is another common feature of the condition. It is unclear how reduced PI3K signaling is associated with the other signs and symptoms of SHORT syndrome.

Cancers

Some gene variants, called somatic variants, are not inherited and are present only in certain cells. Somatic PIK3R1 gene variants have been identified in some cancers of the uterine lining (endometrial cancers) and in a form of brain cancer called glioblastoma. Less commonly, somatic variants in the PIK3R1 gene have been found in cancers of the colon, ovary, and breast.

Cancer-associated changes in the PIK3R1 gene alter the regulatory subunit such that it can no longer control the activity of PI3K, which increases PI3K signaling dramatically. Because the genetic changes enhance the activity of the enzyme, they are classified as gain-of-function variants. Increased PI3K signaling appears to promote the uncontrolled cell growth and division that is characteristic of cancerous tumors. It is unclear why these variants seem to be more common in some types of cancer than in others.

Other Names for This Gene

• p85
• p85-ALPHA
• P85A_HUMAN
• phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
• phosphatidylinositol 3-kinase regulatory subunit alpha
• phosphatidylinositol 3-kinase-associated p-85 alpha
• phosphoinositide-3-kinase regulatory subunit
• PI3-kinase subunit p85-alpha
• PI3K regulatory subunit alpha

Genomic Location

PIK3R1 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 PIK3R1 gene dominates the normal PIK3R1 gene from the other parent. Dominant inheritance also means that most families with PIK3R1 disease have affected relatives in each generation on the side of the family with the mutation. Importantly, however, not all people with the mutation have severe disease.

Unlike mutations that run in a family, some PIK3R1 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 PIK3R1 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 PIK3R1 disease or pass on the mutation.

PIK3R1 disease ranges in severity and can cause many symptoms. Most of these symptoms can be treated successfully. People with PIK3R1 disease may experience the following:

• Recurrent infections, particularly of the respiratory tract, which can lead to airway damage (e.g., pneumonitis, bronchiectasis).
• Lymphoproliferation, or the buildup of immune cells called lymphocytes, which leads to enlarged lymph nodes (lymphadenopathy) and an enlarged spleen (splenomegaly).
• Chronic viremia, or high levels of viruses such as Epstein-Barr virus (EBV) and cytomegalovirus in the blood.
• Lymphoid hyperplasia, or development of distinctive lymphoid nodules—small collections of lymph tissue—on mucosal surfaces such as the airways or gastrointestinal tract.
• Cytopenias, or reductions in the number of blood cells. Autoimmune cytopenias occur when the immune system attacks and destroys the body’s blood cells. Cytopenias can cause fatigue, increased risk of bleeding, and slow wound healing.
• EBV-driven lymphoma, a type of cancer associated with EBV infection.
• Small stature or growth retardation.
• Developmental delays (when a child does not meet his or her developmental milestones at expected times).

Importantly, the severity of PIK3R1 disease varies. Some people with PIK3R1 disease have many medical problems while others experience minimal symptoms. This variation in disease severity, called variable expressivity, can be striking, even within the same family. Symptoms also may change over time. This variation may be explained by differences in lifestyle, exposures, treatments, or other genes.

The clinical symptoms of PIK3R1 disease are caused by immune system abnormalities. These include too few of some immune cell types and too many of other types. For example, people with PIK3R1 disease typically have too few of a type of memory cells and too many transitional B cells, effector T cells, and senescent T cells. Many patients also have differences in their immunoglobulin, or antibody, concentrations. For example, most people with PIK3R1 disease have slightly elevated levels of the IgM subtype and reduced levels of IgA and IgG.

Once a diagnosis is made, treatment for PIK3R1 disease is based on a person’s clinical condition. Some symptoms can be managed with immunoglobulin replacement and preventive use of antibiotics. Some patients have been treated with a medication that targets and reduces B cells to minimize lymphopro liferation or autoimmune cytopenias. Researchers have had some success treating PIK3R1 disease with medications that inhibit the immune system pathway that is overactivated in people with the disease. In early studies, this strategy reduced swelling of the lymph nodes (lymphadenopathy). More research is needed to determine the most effective timing and dosage of this medication and to investigate other treatment options. In rare and severe cases, bone marrow transplantation may be an option.

Living with PIK3R1 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 the disease and about how the family is dealing with it so misconceptions can be identified and corrected and children can learn to identify and cope with their reactions. Some children have to work hard to develop their selfconfidence and sense of security. Children need to be reminded that they have many positive characteristics, especially when their appearance attracts attention (for example, because of enlarged lymph nodes in the neck).

Some children who have siblings with this disease worry about their brother or sister being in pain or dying. 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 or similar diseases. Counseling also can help families cope with the challenges of a chronic illness.

At the same time, many families say that PIK3R1 disease has brought them closer together. Through this disease, family members learn about controllable and uncontrollable aspects of life. Although certain aspects of the disease cannot be controlled, how a family responds to the stress of any illness is controllable and an important aspect of managing PIK3R1 disease. Children also learn who they can turn to for support and how to solve problems. Acknowledging both the challenges and opportunities that this chronic illness presents helps children develop resilience.