MITF

MITF gene variants (also called mutations) have also been found in people with an aggressive form of skin cancer called melanoma. Most of these variants are somatic, meaning that they occur during a person's lifetime and are present only in  cells that give rise to the melanoma. Occasionally the variant is inherited and is found in every cell of the body (known as a germline variant). 

Some of the MITF gene variants associated with melanoma increase cell growth and division (proliferation) directly. Other variants have an indirect effect, increasing the activity (expression) of other genes involved in proliferation and resulting in the abnormal cell growth that occurs in melanoma.

MITF gene variants have been identified in people with Tietz syndrome, which is characterized by profound hearing loss from birth, fair skin, and light-colored hair. Researchers suggest that Tietz syndrome may be a severe form of Waardenburg syndrome (described below).

The MITF gene variants that cause Tietz syndrome either delete or change a single protein building block (amino acid) in the basic motif region of the melanocyte inducing transcription factor structure. Dimers incorporating the abnormal melanocyte inducing transcription factor cannot be transported into the cell nucleus to bind with DNA. As a result, most of the dimers are unavailable to bind to DNA, which affects the development of melanocytes and the production of melanin. The resulting reduction or absence of melanocytes in the inner ear leads to hearing loss.  Decreased melanin production (hypopigmentation) accounts for the light skin and hair color that are characteristic of Tietz syndrome.

Variants in the MITF gene have been identified in people with Waardenburg syndrome type II, a disorder that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Some MITF gene variants change the amino acids used to make  melanocyte inducing transcription factor, which alters the helix-loop-helix or leucine-zipper motif. Other variants result in an abnormally small version of the protein. Researchers believe that both types of variant disrupt the formation of dimers. Although some dimers are produced, the amount is insufficient for full development of melanocytes. As a result, there is a shortage of melanocytes in certain areas of the skin, hair, eyes, and inner ear.  This shortage leads to hearing loss and the patchy loss of pigmentation associated with Waardenburg syndrome.