Ret Gene

• The RET gene (Rearranged during Transfection) is a proto-oncogene vital for cell growth, differentiation, and survival.
• It encodes a receptor tyrosine kinase that is crucial for the development of the nervous system and kidneys.
• Mutations in the RET gene can lead to both gain-of-function (oncogenic) and loss-of-function disorders.
• Gain-of-function mutations are primarily associated with various forms of cancer, including Multiple Endocrine Neoplasia type 2 (MEN2) and Medullary Thyroid Carcinoma (MTC).
• Loss-of-function mutations are linked to developmental conditions like Hirschsprung disease.

What is the Ret Gene (RET) and Its Function?

The RET gene, an abbreviation for “Rearranged during Transfection,” is a human gene located on chromosome 10. It is classified as a Ret proto-oncogene explained, meaning it typically promotes cell growth and division, but can become an oncogene (cancer-causing gene) if mutated. The RET gene provides instructions for making a protein known as the RET receptor tyrosine kinase. This protein is situated on the surface of cells and acts as a receptor, binding to specific signaling molecules outside the cell.

Upon binding, the RET receptor initiates a cascade of intracellular signaling pathways that are fundamental for various cellular processes. These include cell growth, differentiation, migration, and survival. The role of Ret gene in human health is particularly significant in embryonic development, especially for the formation of the enteric nervous system (which controls the gastrointestinal tract) and kidney development. Proper functioning of the RET gene is therefore crucial for the normal development and maintenance of these vital organ systems.

Ret Gene Mutations and Associated Diseases

Mutations in the RET gene mutations and diseases are well-documented and can lead to a spectrum of human disorders, depending on the nature and location of the genetic alteration. These mutations are broadly categorized into two main types: gain-of-function and loss-of-function mutations.

Gain-of-function mutations cause the RET protein to be constantly active, even in the absence of its normal signaling molecules. This uncontrolled activation promotes excessive cell growth and division, leading to various cancers. The most prominent conditions associated with gain-of-function RET mutations include:

• Multiple Endocrine Neoplasia type 2 (MEN2): A group of inherited disorders characterized by tumors in multiple endocrine glands. MEN2 is further divided into subtypes (MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma or FMTC), all driven by specific RET mutations.
• Medullary Thyroid Carcinoma (MTC): A rare form of thyroid cancer that originates from the parafollicular C cells of the thyroid gland. RET mutations are found in nearly all hereditary cases and a significant percentage of sporadic (non-inherited) cases. According to the American Thyroid Association, germline RET mutations are identified in approximately 25% of all MTC patients.
• Non-Small Cell Lung Cancer (NSCLC): In some cases, RET gene fusions (where a part of the RET gene combines with another gene) can drive tumor growth in NSCLC, making it a target for specific therapies.

Conversely, loss-of-function mutations reduce or eliminate the activity of the RET protein. This deficiency disrupts normal cell development and function, primarily affecting the nervous system. The most notable condition resulting from loss-of-function RET mutations is Hirschsprung disease. This congenital disorder is characterized by the absence of nerve cells (ganglion cells) in parts of the intestine, leading to severe constipation and intestinal obstruction. RET mutations are a major genetic cause of Hirschsprung disease, accounting for a substantial proportion of both familial and sporadic cases, as reported by organizations like the National Organization for Rare Disorders (NORD).