Genes serve as blueprints within our cells, providing instructions for building and maintaining the human body. The KIT gene plays an important part in cellular communication and development, overseeing various biological processes, from the formation of blood cells to the pigmentation of our skin. Understanding the KIT gene offers insights into how our bodies are built and how they can sometimes go awry.
The KIT Gene’s Role
The KIT gene instructs cells to produce a protein called KIT protein, also known as CD117, which belongs to a family of receptor tyrosine kinases. These proteins are located on the surface of cells and relay signals from outside the cell to its interior. When stem cell factor (SCF) binds to the KIT protein, it triggers a cascade of events inside the cell. This activates the KIT protein, initiating various signaling pathways through phosphorylation, a process where phosphate groups are added to other proteins.
The signaling pathways activated by the KIT protein regulate several cellular processes, including cell growth, division, survival, and movement. This signaling is important for the development and functioning of specific cell types. These include blood-forming cells (hematopoietic stem cells), mast cells (involved in immune responses), melanocytes (cells that produce melanin, the pigment responsible for skin, hair, and eye color), and interstitial cells of Cajal (ICCs) in the gastrointestinal tract, which regulate gut movement.
When KIT Goes Awry
When the KIT gene experiences changes, or mutations, its normal function can be disrupted, leading to health consequences. These mutations can result in two types of malfunctions: “gain-of-function” or “loss-of-function.” In a gain-of-function mutation, the KIT protein becomes overactive, signaling continuously even without its normal activator, stem cell factor. This uncontrolled activity can lead to excessive cell growth and proliferation, contributing to various conditions.
Conversely, a loss-of-function mutation means the KIT protein’s activity is reduced or entirely absent. This deficiency can interfere with the normal development, migration, or survival of cells that depend on proper KIT signaling. This lack of function can result in developmental problems, as cells cannot carry out their intended roles effectively. Both types of mutations highlight the KIT gene’s importance in maintaining health.
Associated Health Conditions
Mutations in the KIT gene are linked to a range of health conditions, depending on whether the mutation causes a gain or loss of function. Gastrointestinal Stromal Tumors (GISTs) are an example of conditions driven by gain-of-function KIT mutations. In approximately 80-85% of GIST cases, KIT gene mutations lead to continuous activation of the KIT protein, promoting uncontrolled growth of interstitial cells of Cajal in the gastrointestinal tract. These mutations often occur in exon 11 of the KIT gene, though exon 9 mutations are also observed.
Mastocytosis is another condition associated with gain-of-function KIT mutations, characterized by the abnormal accumulation of mast cells in various tissues. More than 80% of adults with systemic mastocytosis have a specific KIT gene mutation, Asp816Val (D816V), which causes the KIT protein to be constitutively activated, leading to an overproduction of mast cells. This excess can result in symptoms similar to severe allergic reactions, including skin flushing, nausea, and low blood pressure.
On the other hand, loss-of-function mutations in the KIT gene can lead to developmental disorders. Piebaldism is an example, characterized by patches of white skin and hair due to a lack of melanocytes in affected areas. Various KIT gene mutations have been identified in individuals with piebaldism, where the nonfunctional KIT protein disrupts melanocyte migration and proliferation during embryonic development. Some loss-of-function KIT mutations have also been implicated in certain types of infertility or deafness.
Targeting KIT in Medicine
Understanding the KIT gene’s role in both normal physiology and disease has paved the way for targeted therapeutic strategies. Since gain-of-function mutations in the KIT protein drive uncontrolled cell growth in conditions like GIST and Mastocytosis, researchers developed drugs designed to block this abnormal activity. These drugs are known as tyrosine kinase inhibitors (TKIs).
Imatinib (Gleevec) is an example of such a targeted drug. It was one of the first TKIs approved and has revolutionized GIST treatment, particularly for tumors with KIT exon 11 mutations, significantly improving patient outcomes. Imatinib works by inhibiting the overactive KIT protein, slowing or halting tumor growth. However, some KIT mutations, such as the D816V mutation common in Mastocytosis, confer resistance to imatinib, necessitating alternative TKIs like midostaurin or avapritinib. These newer inhibitors are designed to overcome resistance mechanisms and provide effective treatment options for patients with these mutations.