KMT2D

Hundreds of variants (also known as mutations) in the KMT2D gene have been identified in people with Kabuki syndrome, a disorder characterized by distinctive facial features, intellectual disability, and abnormalities affecting other parts of the body.

The KMT2D gene variants associated with Kabuki syndrome change one building block (amino acid) in the lysine-specific methyltransferase 2D enzyme, delete genetic material in the KMT2D gene sequence, or result in a premature stop signal that leads to an abnormally short enzyme. As a result of these changes, the enzyme is nonfunctional. A lack of functional lysine-specific methyltransferase 2D enzyme disrupts its role in histone methylation and impairs proper activation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Although lysine-specific methyltransferase 2D is believed to be a tumor suppressor, a loss of this enzyme's function does not seem to increase cancer risk in people with Kabuki syndrome.

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Some gene variants occur during a person's lifetime. Such changes, which are called somatic variants, are present only in certain cells. Somatic variants in the KMT2D gene have been identified in certain cancers. These include medulloblastomas, which are cancerous brain tumors that occur in childhood, and blood-related cancers called lymphomas. Most of these variants result in an abnormally short, nonfunctional lysine-specific methyltransferase 2D enzyme that cannot perform its role as a tumor suppressor, resulting in the development of cancer.

Increased amounts of lysine-specific methyltransferase 2D and altered distribution of the enzyme within cells have been identified in cancerous tumors of the breast and colon. It is unknown whether these changes result primarily from increased activity (overexpression) of the KMT2D gene, extra copies of the gene in tumor cells, altered stability or processing of the enzyme, or other mechanisms. Excess amounts of lysine-specific methyltransferase 2D may disrupt the regulation of other genes. As a result, cells may grow and divide too quickly or in an uncontrolled way, leading to cancer.