RET

RET (Rearranged during Transfection)

The RET proto-oncogene is a critical component in the development and function of the human nervous system. It encodes a receptor tyrosine kinase that is essential for the normal development of the enteric nervous system and kidneys. Mutations in the RET gene are associated with several human diseases, including multiple endocrine neoplasia type 2 (MEN2), Hirschsprung's disease, and medullary thyroid carcinoma.

Structure and Function

The RET gene is located on chromosome 10q11.2 and consists of 21 exons. The protein product of the RET gene is a receptor tyrosine kinase that is activated by binding to glial cell line-derived neurotrophic factor (GDNF) family ligands. This interaction is mediated by a co-receptor, GFRα (GDNF family receptor alpha).

Upon ligand binding, RET undergoes dimerization and autophosphorylation, which activates its kinase activity. This activation triggers downstream signaling pathways, including the MAPK/ERK and PI3K/AKT pathways, which are involved in cell proliferation, differentiation, and survival.

Clinical Significance

Multiple Endocrine Neoplasia Type 2 (MEN2)

Mutations in the RET gene are a well-known cause of MEN2, an autosomal dominant disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. MEN2 is further classified into MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) based on the specific clinical features and mutations involved.

Hirschsprung's Disease

Hirschsprung's disease is a congenital disorder caused by the absence of ganglion cells in the distal colon, leading to bowel obstruction. Mutations in the RET gene are one of the genetic causes of this disease, highlighting the gene's role in the development of the enteric nervous system.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a type of thyroid cancer that arises from parafollicular C cells. Germline mutations in the RET gene are responsible for hereditary forms of MTC, while somatic mutations can be found in sporadic cases.

Genetic Testing and Management

Genetic testing for RET mutations is crucial for the early diagnosis and management of conditions like MEN2. Identifying RET mutations allows for prophylactic thyroidectomy in at-risk individuals, significantly reducing the risk of developing medullary thyroid carcinoma.

Research and Therapeutic Implications

Targeted therapies against RET mutations are an area of active research. Tyrosine kinase inhibitors (TKIs) such as vandetanib and cabozantinib have been approved for the treatment of advanced medullary thyroid carcinoma. Ongoing research aims to develop more selective RET inhibitors with fewer side effects.

Also see

• Proto-oncogene
• Tyrosine kinase
• Multiple endocrine neoplasia
• Hirschsprung's disease
• Medullary thyroid carcinoma