NOTCH1 gene

The NOTCH1 gene provides instructions for making a protein essential for cell development, growth, and specialization, and its dysfunction is linked to various genetic syndromes and cancers.

Normal Function

The NOTCH1 gene provides instructions for making a protein called Notch1, a member of the Notch family of receptors. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand to the Notch1 receptor sends signals that are important for the normal development of many tissues throughout the body, both before and after birth.

Notch1 signaling helps determine the specialization of cells into certain cell types (cell fate determination) and plays a role in cell growth and division (proliferation), maturation (differentiation), and self-destruction (apoptosis). Because of these diverse functions, the gene acts as both an oncogene (which can promote cancer when mutated) and a tumor suppressor (which prevents uncontrolled cell growth).

Health Conditions Related to Genetic Changes

Adams-Oliver syndrome

At least 15 mutations in the NOTCH1 gene have been found to cause Adams-Oliver syndrome, characterized by areas of missing skin (aplasia cutis congenita), usually on the scalp, and malformations of the hands and feet. These mutations may lead to a shortage of functional Notch1 protein or alter its structure, impairing its ability to function. Loss of Notch1 signaling is thought to underlie associated blood vessel and heart abnormalities.

Head and neck squamous cell carcinoma

Mutations in the NOTCH1 gene are found in about 15 percent of head and neck squamous cell carcinomas (HNSCC). These are acquired somatic mutations found only in tumor cells. By reducing or eliminating functional Notch1 protein, these mutations disable the gene's tumor suppressor function, allowing cells to grow and divide without control.

Critical congenital heart disease

NOTCH1 gene mutations are involved in critical congenital heart disease, which includes structural abnormalities affecting the heart chambers, valves, or the large blood vessels leading into and out of the heart, such as the aorta and pulmonary artery.

Other disorders

NOTCH1 mutations can impair heart development, specifically contributing to bicuspid aortic valve, a condition where the aortic valve has only two flaps instead of three. This condition increases the risk of thoracic aortic aneurysm, aortic dissection, and valve calcification.

Other cancers

In cancers such as T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-small cell lung cancer, NOTCH1 mutations abnormally activate Notch1 signaling. This increased activity leads to uncontrolled cell growth and division.