2.1. PDGFRB-associated chronic eosinophilic leukemia

Genetic rearrangements (translocations) involving the PDGFRB gene cause a type of cancer of blood-forming cells called PDGFRB-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell. The most common of these translocations brings together part of the PDGFRB gene with another gene called ETV6, whose function is to turn off gene activity. Together, these pieces create the ETV6-PDGFRB fusion gene. Occasionally, genes other than ETV6 are fused with the PDGFRB gene. The translocations that lead to these fusion genes are somatic mutations, which are acquired during a person's lifetime and occur initially in a single cell. This cell continues to grow and divide, producing a group of cells with the same mutation (a clonal population).

The protein produced from the ETV6-PDGFRB fusion gene (as well as other PDGFRB fusion genes) functions differently than the proteins normally produced from the individual genes. The ETV6/PDGFRβ fusion protein does not require ligand binding to be activated and cannot bind to DNA to turn off gene activity. As a result, signaling pathways are constantly turned on (constitutively activated) and gene activity is increased, which increases the proliferation and survival of cells.

When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of eosinophils (and occasionally other white blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRB-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

2.2. Primary familial brain calcification

At least six mutations in the PDGFRB gene have been found to cause primary familial brain calcification. This condition is characterized by abnormal deposits of calcium (calcification) in the brain, which can lead to movement and psychiatric problems. These mutations change single protein building blocks (amino acids) in the PDGFRβ protein. These changes impair the protein's signaling ability.

It is unclear how PDGFRB gene mutations cause primary familial brain calcification. The altered signaling may result in an abnormally large amount of calcium entering the cells that line blood vessels in the brain, leading to calcification of these blood vessels. Alternatively, changes in PDGFRB signaling could disrupt processes that regulate levels of phosphate and calcium in brain cells, leading to the formation of calcium deposits. In the brain, the excess phosphate combines with calcium and forms deposits.

The PDGFRB gene is active (expressed) throughout the body; it is unclear why the effects of these mutations are limited to structures deep within the brain that help start and control movement (basal ganglia) and to other brain regions that are involved in primary familial brain calcification.

2.3. Other disorders

Additional mutations in the PDGFRB gene cause a variety of disorders including infantile myofibromatosis; Kosaki overgrowth syndrome; and premature aging syndrome, Penttinen type.

Infantile myofibromatosis is a muscle disorder that causes the formation of multiple noncancerous (benign) tumors in the skin, muscles, or bones. These tumors are generally present at birth or in early infancy.

Kosaki overgrowth syndrome is characterized by above-average height and large hands and feet. Affected individuals have highly stretchy (elastic) and fragile skin. People with this condition also have distinctive facial features and brain abnormalities that result in intellectual disability and psychological problems.

Premature aging syndrome, Penttinen type is characterized by a lack of fatty tissue under the skin (lipoatrophy). This lack of fat, together with thin, wrinkled skin and veins visible beneath the skin, makes affected individuals look older than their biological age.

In all of these conditions, PDGFRB gene mutations result in increased cell signaling. While it is unclear how mutations in one gene can lead to so many different conditions, it is thought that particular mutations may affect different signaling pathways, leading to changes in specific body systems.