Tietz syndrome is a disorder characterized by profound hearing loss from birth, fair skin, and light-colored hair. The hearing loss in affected individuals is caused by abnormalities of the inner ear (sensorineural hearing loss) and is present from birth. Although people with Tietz syndrome are born with white hair and very pale skin, their hair color often darkens over time to blond or red. The skin of affected individuals, which sunburns very easily, may tan slightly or develop reddish freckles with limited sun exposure; however, their skin and hair color remain lighter than those of other members of their family.

Tietz syndrome also affects the eyes. The colored part of the eye (the iris) in affected individuals is blue, and specialized cells in the eye called retinal pigment epithelial cells lack their normal pigment. The retinal pigment epithelium nourishes the retina, the part of the eye that detects light and color. The changes to the retinal pigment epithelium are generally detectable only by an eye examination; it is unclear whether the changes affect vision.

Tietz syndrome is caused by mutations in the MITF gene. This gene provides instructions for making a protein that plays a role in the development, survival, and function of certain types of cells. Molecules of the MITF protein attach (bind) to each other or with other proteins that have a similar structure, creating a two-protein unit (dimer). The dimer attaches to specific areas of DNA and helps control the activity of particular genes. On the basis of this action, the MITF protein is called a transcription factor.

The MITF protein helps control the development and function of pigment-producing cells called melanocytes. Within these cells, this protein controls production of the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in the inner ear and play an important role in hearing. Additionally, the MITF protein regulates the development of the retinal pigment epithelium.

MITF gene mutations that cause Tietz syndrome either delete or change a single protein building block (amino acid) in an area of the MITF protein known as the basic motif region. Dimers incorporating the abnormal MITF protein 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 and the retinal pigment epithelium changes that are characteristic of Tietz syndrome.

Researchers suggest that Tietz syndrome may represent a severe form of a disorder called Waardenburg syndrome, which can also be caused by MITF gene mutations.

Normal Function

The MITF gene provides instructions for making a protein called melanocyte inducing transcription factor. This protein plays a role in the development, survival, and function of certain types of cells. To carry out this role, the protein attaches to specific areas of DNA and helps control the activity of particular genes. On the basis of this action, the protein is called a transcription factor.

Melanocyte inducing transcription factor helps control the development and function of pigment-producing cells called melanocytes. Within these cells, this protein controls production of the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in the inner ear and play an important role in hearing. Additionally, melanocyte inducing transcription factor regulates the development of specialized cells in the eye called retinal pigment epithelial cells. These cells nourish the retina, the part of the eye that detects light and color. Some research indicates that melanocyte inducing transcription factor also regulates the development of cells that break down and remove bone (osteoclasts) and cells that play a role in allergic reactions (mast cells).

The structure of melanocyte inducing transcription factor includes three critically important regions. Two of the regions, called the helix-loop-helix motif and the leucine-zipper motif, are critical for protein interactions. These motifs allow molecules of melanocyte inducing transcription factor to interact with each other or with other proteins that have a similar structure, creating a two-protein unit (dimer) that functions as a transcription factor. The other region, known as the basic motif, binds to specific areas of DNA, allowing the dimer to control gene activity.

Health Conditions Related to Genetic Changes

Melanoma

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.

Tietz syndrome

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.

Waardenburg 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.

Other Names for This Gene

• homolog of mouse microphthalmia
• melanogenesis associated transcription factor
• microphthalmia-associated transcription factor
• MITF_HUMAN
• WS2A

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

• Severe, bilateral (both ears) sensorineural hearing loss
• Fair skin
• Light-colored hair
• Blue eyes

Tietz syndrome is a rare disorder; its exact prevalence is unknown. Only a few affected families have been described in the medical literature.