EP300

More than 80 mutations in the EP300 gene have been identified in people with Rubinstein-Taybi syndrome, a condition characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. Genetic changes in the EP300 gene cause a small percentage of cases of this condition. Some mutations lead to the production of an abnormally small, nonfunctional version of the p300 protein, while other mutations prevent one copy of the gene from making any protein at all. These genetic changes all result in the loss of one functional copy of the EP300 gene in each cell, which reduces the amount of p300 protein by half. Although researchers are uncertain how a reduction in the amount of this protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that changes in the EP300 gene disrupt normal development before and after birth. Problems with development of multiple systems are thought to underlie the features of Rubinstein-Taybi syndrome.

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Mutations in the EP300 gene are a very rare cause of a condition called Menke-Hennekam syndrome. While this condition shares some features with Rubinstein-Taybi syndrome (described above), such as intellectual disability and growth delays, individuals with Menke-Hennekam syndrome do not have the facial features and thumb and toe abnormalities characteristic of Rubinstein-Taybi syndrome. Other features of Menke-Hennekam syndrome are variable and can include vision or hearing impairment, recurrent seizures (epilepsy), frequent airway infections, and autistic behaviors that affect communication.

The EP300 gene mutations that cause Menke-Hennekam syndrome occur in regions of the gene known as exon 30 or exon 31. They result in changes to single protein building blocks (amino acids) in the p300 protein. Researchers suggest that these changes give the altered protein a new function, which disrupts development and causes the signs and symptoms of Menke-Hennekam syndrome.

Rarely, chromosomal rearrangements (translocations) involving chromosome 22 have been associated with certain types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In cancer cells, translocations can disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosome 8 and chromosome 22 in several people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer.

Somatic mutations in the EP300 gene have been identified in several other types of cancer. These mutations prevent the gene from producing any functional protein. Cells without the p300 protein cannot effectively restrain growth and division, allowing cancerous tumors to develop and grow. Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers. These genetic changes could help predict whether prostate tumors will increase in size or spread to other parts of the body.