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PIK3R1 Gene: Overview and Associated Health Conditions
The PIK3R1 gene provides instructions for making a regulatory subunit of the phosphatidylinositol 3-kinase (PI3K) enzyme, which is essential for cell growth, survival, and signaling. Variants in this gene are linked to immune disorders, SHORT syndrome, and certain cancers.
Normal Function
The PIK3R1 gene produces a subunit of the enzyme phosphatidylinositol 3-kinase (PI3K). The primary role of this subunit is to regulate the enzyme's activity. Several slightly different versions of this regulatory subunit are produced from the PIK3R1 gene, with the most abundant version known as p85 alpha (p85α).
PI3K is a kinase, meaning it adds a phosphate group (a cluster of oxygen and phosphorus atoms) to other proteins through a process called phosphorylation. By phosphorylating specific signaling molecules, PI3K triggers a series of reactions that transmit chemical signals within cells. This signaling pathway is critical for various cellular activities, including:
- Cell growth and division (proliferation)
- Cell movement (migration)
- Production of new proteins
- Transport of materials within cells
- Cell survival
Research suggests that PI3K signaling may also be involved in how cells regulate several hormones. Notably, it may play a role in the function of insulin, which helps control blood glucose (blood sugar) levels, and in the maturation of fat cells (adipocytes).
Health Conditions Related to Genetic Changes
Activated PI3K-delta Syndrome
Variants (mutations) in the PIK3R1 gene cause a form of immune disorder known as activated PI3K-delta syndrome type 2. Individuals with this condition typically experience recurrent bacterial infections of the respiratory tract and chronic viral infections.
These variants lead to an altered p85α protein, which is sometimes abnormally short. They are classified as gain-of-function variants because the PI3K-delta enzyme containing the altered subunit is frequently overactive. This overactive signaling alters the growth of specific immune system cells:
- T cells mature and die too quickly.
- B cells are blocked from maturing at an early stage and likely self-destruct, leaving them unable to respond to foreign invaders.
The resulting lack of functional B and T cells makes it difficult for affected individuals to fight off bacterial and viral infections. In some cases, overactive PI3K-delta signaling can stimulate the abnormal proliferation of white blood cells. Additionally, activated PI3K-delta syndrome type 2 is associated with an increased risk of developing lymphoma, a form of blood cell cancer.
SHORT Syndrome
Variants in the PIK3R1 gene have also been reported to cause a condition known as SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay). This condition affects multiple parts of the body, including the skin, eyes, teeth, and joints.
The most common variant changes a single amino acid in the regulatory subunit of PI3K. These changes alter the structure of the subunit, reducing the enzyme's ability to participate in cell signaling. Consequently, these are described as loss-of-function variants.
Researchers are investigating how these variants lead to the specific features of SHORT syndrome. Potential connections include:
- Insulin resistance and diabetes: PI3K's role in insulin activity may be related to blood glucose regulation issues found in some patients.
- Lipoatrophy: Abnormal adipocyte maturation may contribute to a lack of fatty tissue under the skin.
It remains unclear how reduced PI3K signaling is associated with the other signs and symptoms of SHORT syndrome.
Cancers
Somatic variants—genetic changes that are not inherited and are present only in certain cells—have been identified in the PIK3R1 gene in several types of cancer. These include:
- Endometrial cancers (cancers of the uterine lining)
- Glioblastoma (a form of brain cancer)
- Less commonly, cancers of the colon, ovary, and breast
Cancer-associated changes in the PIK3R1 gene alter the regulatory subunit so that it can no longer control PI3K activity, dramatically increasing PI3K signaling. These are classified as gain-of-function variants. The increased signaling appears to promote the uncontrolled cell growth and division characteristic of cancerous tumors. It is currently unclear why these variants are 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
The PIK3R1 gene is found on chromosome 5.