Adams-Oliver syndrome

At least 15 mutations in the NOTCH1 gene have been found to cause Adams-Oliver syndrome, a condition characterized by areas of missing skin (aplasia cutis congenita), usually on the scalp, and malformations of the hands and feet. These mutations are usually inherited and are present in every cell of the body. Some of the NOTCH1 gene mutations involved in Adams-Oliver syndrome lead to production of an abnormally short protein that is likely broken down quickly, causing a shortage of Notch1. Other mutations change single protein building blocks (amino acids) in the Notch1 protein. These changes are thought to alter the structure of the protein, impairing its ability to function. Loss of Notch1 signaling may underlie blood vessel and heart abnormalities in people with Adams-Oliver syndrome. However, while these types of abnormalities are more common in affected individuals with NOTCH1 gene mutations than in those with a different gene mutation, some people with Notch1-related Adams-Oliver syndrome do not have blood vessel or heart abnormalities. It is not clear how loss of Notch1 function leads to the scalp and limb abnormalities characteristic of the condition. Researchers suggest these features may be due to abnormal blood vessel development before birth.

Head and neck squamous cell carcinoma

Mutations in the NOTCH1 gene have been found in about 15 percent of head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. NOTCH1 gene mutations associated with this condition are acquired during a person's lifetime and are found only in tumor cells; these changes are known as somatic mutations. Mutations in the NOTCH1 gene may reduce or eliminate production of functional Notch1 protein or lead to production of a protein that is unable to participate in cell signaling. Without the tumor suppressor function of the Notch1 protein, cells can grow and divide without control, leading to tumor formation.

Critical congenital heart disease

NOTCH1 gene mutations are involved in critical congenital heart disease. Individuals with this condition have one or more specific heart abnormalities that affect the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.

Other disorders

Mutations in the NOTCH1 gene can impair normal heart development before birth, causing abnormalities of the heart and related structures. One such abnormality occurs in the valve that connects the aorta to the heart (the aortic valve). The aorta is the large blood vessel that distributes blood from the heart to the rest of the body. The aortic valve normally has three flaps, or cusps, that open to let blood leave the heart and come together to prevent blood from reentering the heart. However, in about 1 to 2 percent of people, the aortic valve has only two flaps, which is known as a bicuspid aortic valve. NOTCH1 gene mutations appear to be involved in 4 to 10 percent of bicuspid aortic valve cases.

Individuals with a bicuspid aortic valve are at a higher than normal risk of developing other aortic abnormalities, such as a bulge in the wall of the aorta (thoracic aortic aneurysm) or a sudden tearing of the layers in the aorta wall (aortic dissection). In addition, accumulation of calcium on the aortic valve can occur in people with a bicuspid aortic valve. Researchers suspect that NOTCH1 gene mutations also play a role in the development of thoracic aortic aneurysms and in calcification of the valve.

Other cancers

NOTCH1 gene mutations have been found in other types of cancer, particularly blood cell cancers called T-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia, and a type of lung cancer called non-small cell lung cancer. Unlike in HNSCC (described above), the NOTCH1 gene mutations found in these cancers abnormally turn on (activate) Notch1 signaling. The increased activity can lead to uncontrolled cell growth and division, which can result in the development of cancer. Researchers are working to understand how both activating and inactivating NOTCH1 gene mutations can lead to cancer development.