Oculocutaneous albinism is a group of conditions that affect coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have very fair skin and white or light-colored hair. Long-term sun exposure greatly increases the risk of skin damage and skin cancers, including an aggressive form of skin cancer called melanoma, in people with this condition. Oculocutaneous albinism also reduces pigmentation of the colored part of the eye (the iris) and the light-sensitive tissue at the back of the eye (the retina). People with this condition usually have vision problems such as reduced sharpness; rapid, involuntary eye movements (nystagmus); and increased sensitivity to light (photophobia).

Researchers have identified multiple types of oculocutaneous albinism, which are distinguished by their specific skin, hair, and eye color changes and by their genetic cause. Oculocutaneous albinism type 1 is characterized by white hair, very pale skin, and light-colored irises. Type 2 is typically less severe than type 1; the skin is usually a creamy white color and hair may be light yellow, blond, or light brown. Type 3 includes a form of albinism called rufous oculocutaneous albinism, which usually affects dark-skinned people. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Type 3 is often associated with milder vision abnormalities than the other forms of oculocutaneous albinism. Type 4 has signs and symptoms similar to those seen with type 2.

Several additional types of this disorder have been proposed, each affecting one or a few families.

Overall, an estimated 1 in 20,000 people worldwide are born with oculocutaneous albinism. The condition affects people in many ethnic groups and geographical regions. Types 1 and 2 are the most common forms of this condition; types 3 and 4 are less common. Type 2 occurs more frequently in African Americans, some Native American groups, and people from sub-Saharan Africa. Type 3, specifically rufous oculocutaneous albinism, has been described primarily in people from southern Africa. Studies suggest that type 4 occurs more frequently in the Japanese and Korean populations than in people from other parts of the world.

Oculocutaneous albinism can result from variants (also known as mutations) in several genes, including TYR, OCA2, TYRP1, and SLC45A2. Variants in the TYR gene cause type 1; variants in the OCA2 gene cause type 2; variants in the TYRP1 gene cause type 3; and variants in the SLC45A2 gene cause type 4. Variants in additional genes likely underlie the other forms of this disorder. The genes associated with oculocutaneous albinism are involved in producing a pigment called melanin, which is the substance that gives skin, hair, and eyes their color. In the retina, melanin also plays a role in normal vision. Variants in any of these genes disrupt the ability of cells to make melanin, which reduces pigmentation in the skin, hair, and eyes. A lack of melanin in the retina leads to the vision problems characteristic of oculocutaneous albinism.

Alterations in the MC1R gene can change the appearance of people with oculocutaneous albinism type 2. This gene helps regulate melanin production and is responsible for some normal variation in pigmentation. People with genetic changes in both the OCA2 and MC1R genes have many of the usual features of oculocutaneous albinism type 2, including light-colored eyes and vision problems; however, they typically have red hair instead of the usual yellow, blond, or light brown hair seen with this condition.

Some individuals with oculocutaneous albinism do not have variants in any of the known genes. In these people, the genetic cause of the condition is unknown.

Normal Function

The MC1R gene provides instructions for making a protein called the melanocortin 1 receptor. This receptor plays an important role in normal pigmentation. The receptor is primarily located on the surface of melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Melanocytes make two forms of melanin, eumelanin and pheomelanin. The relative amounts of these two pigments help determine the color of a person's hair and skin. People who produce mostly eumelanin tend to have brown or black hair and dark skin that tans easily. Eumelanin also protects skin from damage caused by ultraviolet (UV) radiation in sunlight. People who produce mostly pheomelanin tend to have red or blond hair, freckles, and light-colored skin that tans poorly. Because pheomelanin does not protect skin from UV radiation, people with more pheomelanin have an increased risk of skin damage caused by sun exposure.

The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. When the receptor is activated, it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin.

Common variations (polymorphisms) in the MC1R gene are associated with normal differences in skin and hair color. Certain genetic variations are most common in people with red hair, fair skin, freckles, and an increased sensitivity to sun exposure. These MC1R polymorphisms reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production, causing melanocytes to make mostly pheomelanin. Although MC1R is a key gene in normal human pigmentation, researchers believe that the effects of other genes also contribute to a person's hair and skin coloring.

The melanocortin 1 receptor is also active in cells other than melanocytes, including cells involved in the body's immune and inflammatory responses. The receptor's function in these cells is unknown.

Health Conditions Related to Genetic Changes

Melanoma

Certain variations in the MC1R gene increase the risk of developing melanoma, a type of skin cancer that begins in melanocytes. These variations reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production in melanocytes, resulting in fair skin. Because eumelanin normally protects skin from the harmful effects of UV radiation, a lack of this pigment leaves skin more vulnerable to damage from sun exposure. Skin damage caused by UV radiation from the sun is a major risk factor for developing melanoma.

Studies suggest that other variations in the MC1R gene may also increase the risk of developing melanoma in the absence of UV radiation-related skin damage. In these cases, melanomas can occur in people of dark or light skin coloring. These cancers are often associated with mutations in additional genes related to melanoma risk, such as the BRAF and CDKN2A genes. Researchers are working to explain the complex relationship among MC1R variations, other genetic and environmental factors, and melanoma risk.

Oculocutaneous albinism

Certain genetic changes in the MC1R gene modify the appearance of people with oculocutaneous albinism type 2. This form of albinism, which is caused by mutations in the OCA2 gene, is characterized by fair hair, light-colored eyes, creamy white skin, and vision problems. People with genetic changes in both the OCA2 and MC1R genes have many of the usual features of oculocutaneous albinism type 2; however, they typically have red hair instead of the usual yellow, blond, or light brown hair seen with this condition.

Other Names for This Gene

• MC1-R
• melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
• Melanocortin-1 receptor
• melanocyte stimulating hormone receptor
• melanotropin receptor
• MSH-R
• MSHR_HUMAN

Genomic Location

Normal Function

The OCA2 gene (formerly called the P gene) provides instructions for making a protein called the P protein. This protein is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Although the exact function of the P protein is unknown, it is essential for normal pigmentation and is likely involved in the production of melanin. Within melanocytes, the P protein may transport molecules into and out of structures called melanosomes (where melanin is produced). Researchers believe that this protein may also help regulate the relative acidity (pH) of melanosomes. Tight control of pH is necessary for most biological processes.

Health Conditions Related to Genetic Changes

Angelman syndrome

The OCA2 gene is located in a region of chromosome 15 that is often deleted in individuals with Angelman syndrome. A loss of this gene does not cause the characteristic neurologic features of Angelman syndrome; however, people with this condition who are missing one copy of the OCA2 gene tend to have unusually light-colored hair and fair skin. Cells with only one copy of the OCA2 gene make a reduced amount of P protein compared with cells with two functional copies of this gene, which affects the coloring of the hair and skin.

A small percentage of people with Angelman syndrome also have oculocutaneous albinism type 2. This condition occurs when people have two nonfunctional copies of the OCA2 gene in each cell. In addition to a deletion in chromosome 15 that removes one copy of the OCA2 gene, these individuals have a variant (also known as a mutation) in the OCA2 gene on the other copy of chromosome 15. As a result, cells make little or no functional P protein. A lack of P protein disrupts the production of melanin, leading to the characteristic features of albinism.

Oculocutaneous albinism

More than 80 variants in the OCA2 gene have been identified in people with oculocutaneous albinism type 2. People with this form of albinism often have light yellow, blond, or light brown hair; creamy white skin; light-colored eyes; and problems with vision. The most common OCA2 variant is a large deletion in the gene, which is found in many affected individuals of sub-Saharan African heritage. Other OCA2 gene variants, including changes in single DNA building blocks (base pairs) and small deletions, are more common in other populations. Variants in the OCA2 gene disrupt the normal production of melanin, which reduces coloring of the hair, skin, and eyes and affects vision.

Prader-Willi syndrome

The region of chromosome 15 containing the OCA2 gene is often deleted in individuals with Prader-Willi syndrome. A loss of this gene does not cause intellectual disability and the other characteristic features of Prader-Willi syndrome; however, people with this condition who are missing one copy of the OCA2 gene tend to have unusually light-colored hair and fair skin. Cells missing a copy of the OCA2 gene make less P protein than cells with two functional copies of the gene, which affects the coloring of the hair and skin.

Oculocutaneous albinism type 2 also occurs in a small number of people with Prader-Willi syndrome. This condition occurs when people have two nonfunctional copies of the OCA2 gene in each cell. In addition to a deletion in chromosome 15 that removes one copy of the OCA2 gene, these individuals have a variant in the OCA2 gene on the other copy of chromosome 15. As a result, cells make little or no functional P protein. A lack of P protein disrupts the production of melanin, leading to the characteristic features of albinism.

Melanoma

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Other Names for This Gene

• BOCA
• Melanocyte-specific transporter protein
• oculocutaneous albinism II
• oculocutaneous albinism II (pink-eye dilution homolog, mouse)
• P gene
• P_HUMAN
• PED
• Pink-eyed dilution protein homolog

Genomic Location

Normal Function

The SLC45A2 gene (also called MATP) provides instructions for making a protein that is located in specialized cells called melanocytes. These cells produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Although the exact function of the SLC45A2 protein is unknown, it is likely involved in the production of melanin. This protein probably transports molecules necessary for the normal function of melanosomes, which are the structures in melanocytes where melanin is produced. Studies suggest that certain common variations (polymorphisms) in the SLC45A2 gene may be associated with normal differences in skin, hair, and eye coloring.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

More than 20 mutations in the SLC45A2 gene are responsible for oculocutaneous albinism type 4. The most common SLC45A2 mutation in the Japanese population switches a single protein building block (amino acid) in the SLC45A2 protein. Specifically, this mutation replaces the amino acid aspartic acid with the amino acid asparagine at protein position 157 (written as Asp157Asn or D157N). Other mutations, including changes in single amino acids and deletions or insertions of genetic material in the SLC45A2 gene, have also been reported in several populations worldwide. Mutations in this gene reduce or eliminate the function of the SLC45A2 protein in melanin production. Because this protein is important for normal pigmentation, its loss leads to changes in skin, hair, and eye coloration and problems with vision that are characteristic of oculocutaneous albinism type 4.

Melanoma

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Other Names for This Gene

• AIM-1
• AIM1
• MATP
• melanoma antigen AIM1
• membrane associated transporter
• membrane-associated transporter protein
• S45A2_HUMAN
• solute carrier family 45, member 2

Genomic Location

Normal Function

The TYR gene provides instructions for making an enzyme called tyrosinase. This enzyme is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Tyrosinase is responsible for the first step in melanin production. It converts a protein building block (amino acid) called tyrosine to another compound called dopaquinone. A series of additional chemical reactions convert dopaquinone to melanin in the skin, hair follicles, the colored part of the eye (the iris), and the retina.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

More than 100 mutations in the TYR gene have been identified in people with oculocutaneous albinism type 1. These mutations disrupt the normal production of melanin, which reduces coloring of the hair, skin, and eyes and causes problems with vision. Most TYR mutations eliminate the activity of tyrosinase, preventing melanocytes from producing any melanin throughout life. These mutations cause a form of oculocutaneous albinism called type 1A (OCA1A). People with this form of albinism have white hair, light-colored eyes, and very pale skin that does not tan. Other mutations in the TYR gene reduce but do not eliminate tyrosinase activity. These mutations, which allow some melanin to be produced, cause oculocutaneous albinism type 1B (OCA1B). People with type 1B are also born with white hair, light-colored eyes, and pale skin, but hair and eye color often darken over time and skin may tan.

Melanoma

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Other Names for This Gene

• LB24-AB
• Monophenol monooxygenase
• OCA1A
• OCAIA
• SK29-AB
• Tumor Rejection Antigen AB
• TYRO_HUMAN

Genomic Location

Normal Function

The TYRP1 gene provides instructions for making an enzyme called tyrosinase-related protein 1. This enzyme is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Tyrosinase-related protein 1 is involved in the production of melanin, although its exact functions are unclear. Studies suggest that this enzyme may help stabilize tyrosinase, which is the enzyme responsible for the first step in melanin production. Tyrosinase-related protein 1 may also help determine the shape of melanosomes, which are the structures in melanocytes where melanin is produced.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

A small number of mutations in the TYRP1 gene have been found to cause oculocutaneous albinism type 3. This condition includes a form of albinism called rufous oculocutaneous albinism, which has been described primarily in dark-skinned people from southern Africa. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Two TYRP1 mutations are known to cause this form of albinism in individuals from Africa. One mutation replaces a protein building block (amino acid) in tyrosine-related protein 1 with a signal that prematurely stops protein production. This mutation, written as Ser166Ter or S166X, affects the amino acid serine at protein position 166. The other mutation, written as 368delA, deletes a single DNA building block from the TYRP1 gene. Other alterations in this gene have been reported in a few affected people of non-African heritage. Most TYRP1 mutations lead to the production of an abnormally short, nonfunctional version of tyrosinase-related protein 1. Because this enzyme plays a role in normal pigmentation, its loss leads to the changes in skin, hair, and eye coloration that are characteristic of oculocutaneous albinism.

Melanoma

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Other Names for This Gene

• b-PROTEIN
• CAS2
• Catalase B
• CATB
• DHICA oxidase
• Glycoprotein 75
• GP75
• TRP
• TRP-1
• tyrosinase-related protein 1
• TYRP
• TYRP1_HUMAN

Genomic Location

Oculocutaneous albinism is inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have variants. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they do not show signs and symptoms of the condition.