Hermansky-Pudlak syndrome is a disorder characterized by a condition called oculocutaneous albinism, which causes abnormally light coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have fair skin and white or light-colored hair. People with this disorder have a higher than average risk of skin damage and skin cancers caused by long-term sun exposure. Oculocutaneous albinism reduces pigmentation of the colored part of the eye (iris) and the light-sensitive tissue at the back of the eye (retina). Reduced vision, rapid and involuntary eye movements (nystagmus), and increased sensitivity to light (photophobia) are also common in oculocutaneous albinism. In Hermansky-Pudlak syndrome, these vision problems usually remain stable after early childhood.

People with Hermansky-Pudlak syndrome also have problems with blood clotting (coagulation) that lead to easy bruising and prolonged bleeding.

Some individuals with Hermansky-Pudlak syndrome develop breathing problems due to a lung disease called pulmonary fibrosis, which causes scar tissue to form in the lungs. The symptoms of pulmonary fibrosis usually appear during an individual's early thirties and rapidly worsen. Individuals with Hermansky-Pudlak syndrome who develop pulmonary fibrosis often do not live for more than a decade after they begin to experience breathing problems.

Other, less common features of Hermansky-Pudlak syndrome include inflammation of the large intestine (granulomatous colitis) and kidney failure.

There are nine different types of Hermansky-Pudlak syndrome, which can be distinguished by their signs and symptoms and underlying genetic cause. Types 1 and 4 are the most severe forms of the disorder. Types 1, 2, and 4 are the only types associated with pulmonary fibrosis. Individuals with type 3, 5, or 6 have the mildest symptoms. Little is known about the signs, symptoms, and severity of types 7, 8, and 9.

At least nine genes are associated with Hermansky-Pudlak syndrome. These genes provide instructions for making proteins that are used to make four distinct protein complexes. These protein complexes play a role in the formation and movement (trafficking) of a group of cell structures called lysosome-related organelles (LROs). LROs are very similar to compartments within the cell called lysosomes, which digest and recycle materials. However, LROs perform specialized functions and are found only in certain cell types. LROs have been identified in pigment-producing cells (melanocytes), blood-clotting cells (platelets), and lung cells.

Mutations in the genes associated with Hermansky-Pudlak syndrome prevent the formation of LROs or impair the functioning of these cell structures. In general, mutations in genes that involve the same protein complex cause similar signs and symptoms. People with this syndrome have oculocutaneous albinism because the LROs within melanocytes cannot produce and distribute the substance that gives skin, hair, and eyes their color (melanin). Bleeding problems are caused by the absence of LROs within platelets, which affects the ability of platelets to stick together and form a blood clot. Mutations in some of the genes that cause Hermansky-Pudlak syndrome affect the normal functioning of LROs in lung cells, leading to pulmonary fibrosis.

Mutations in the HPS1 gene cause approximately 75 percent of the Hermansky-Pudlak syndrome cases from Puerto Rico. About 45 percent of affected individuals from other populations have mutations in the HPS1 gene. Mutations in the HPS3 gene are found in about 25 percent of affected people from Puerto Rico and in approximately 20 percent of affected individuals from other areas. The other genes associated with Hermansky-Pudlak syndrome each account for a small percentage of cases of this condition.

In some people with Hermansky-Pudlak syndrome, the genetic cause of the disorder is unknown.

Normal Function

The HPS1 gene provides instructions for making a protein that forms part of a complex called biogenesis of lysosome-related organelles complex-3 (BLOC-3). This complex plays a role in the formation of a group of cellular structures called lysosome-related organelles (LROs). In particular, BLOC-3 helps turn on the process by which necessary proteins are transported to LROs during their formation. LROs are very similar to compartments within the cell called lysosomes, which digest and recycle materials. However, LROs perform specialized functions and are found only in certain cell types.

Within pigment-producing cells (melanocytes), LROs called melanosomes produce and distribute melanin, which is the substance that gives skin, hair, and eyes their color. A different type of LRO is found in platelets, the blood cells involved in normal blood clotting. These LROs, called dense granules, release chemical signals that cause platelets to stick together and form a blood clot. LROs are also found in other specialized cells, including certain cells of the lungs.

Health Conditions Related to Genetic Changes

Hermansky-Pudlak syndrome

At least 31 mutations in the HPS1 gene have been found to cause Hermansky-Pudlak syndrome type 1. Individuals with this form of the condition typically have oculocutaneous albinism, a condition characterized by fair skin, light-colored hair and eyes, and poor vision. They may also have bleeding problems and a severe lung disease called pulmonary fibrosis.

The HPS1 gene mutations that cause Hermansky-Pudlak syndrome type 1 impair the normal function of BLOC-3, disrupting the size, structure, and function of LROs in cells throughout the body. The most common mutation causes a duplication of genetic material within the HPS1 gene and is found in people from northwest Puerto Rico. Specifically, this mutation results in an extra 16 DNA building blocks (nucleotides) within the gene (written as 1470_1486dup16).

Because the abnormal melanosomes do not distribute melanin properly, people with Hermansky-Pudlak syndrome have unusually light coloring of the skin, hair, and eyes. The absence of dense granules within platelets leads to bleeding problems in affected individuals. Pulmonary fibrosis may also develop due to abnormal LROs in certain lung cells.

Other Names for This Gene

• BLOC3S1
• Hermansky-Pudlak syndrome 1
• Hermansky-Pudlak syndrome 1 protein
• Hermansky-Pudlak syndrome 1 protein isoform a
• Hermansky-Pudlak syndrome 1 protein isoform c
• Hermansky-Pudlak syndrome type 1
• HPS
• HPS1_HUMAN
• MGC5277

Genomic Location

Normal Function

The HPS3 gene provides instructions for making a protein that forms part of a complex called biogenesis of lysosome-related organelles complex-2 (BLOC-2). This complex plays a role in the formation of a group of cellular structures called lysosome-related organelles (LROs). In particular, BLOC-2 controls the sorting and transport of proteins into LROs during their formation. LROs are very similar to compartments within the cell called lysosomes, which digest and recycle materials. However, LROs perform specialized functions and are found only in certain cell types.

Within pigment-producing cells (melanocytes), LROs called melanosomes produce and distribute melanin, which is the substance that gives skin, hair, and eyes their color. A different type of LRO is found in platelets, the blood cells involved in normal blood clotting. These LROs, called dense granules, release chemical signals that cause platelets to stick together and form a blood clot.

Health Conditions Related to Genetic Changes

Hermansky-Pudlak syndrome

At least 7 mutations in the HPS3 gene have been found to cause Hermansky-Pudlak syndrome type 3, which is a mild form of the condition. Affected individuals typically have oculocutaneous albinism, a condition characterized by fair skin, light-colored hair and eyes, and poor vision. They may also have bleeding problems. The HPS3 gene mutations that cause Hermansky-Pudlak syndrome type 3 impair the normal function of BLOC-2, disrupting the size, structure, and function of LROs in cells throughout the body.

One common mutation results in a deletion of genetic material within the HPS3 gene. This deletion includes approximately 3,900 DNA building blocks (nucleotides) and is known as the 3.9kb deletion. It is also written as 339_4260del3904. This mutation, which is found in affected individuals from the central region of Puerto Rico, prevents the production of any HPS3 protein.

Another mutation in the HPS3 gene has been found in people with Central and Eastern European (Ashkenazi) Jewish background. This mutation, called a splice-site mutation, disrupts the way the gene's instructions are used to make the protein. This mutation, which is written as 1163+1G>A, results in an abnormally short protein.

Because the abnormal melanosomes do not distribute melanin properly, people with Hermansky-Pudlak syndrome can develop oculocutaneous albinism. The absence of dense granules within platelets leads to bleeding problems in affected individuals.

Other Names for This Gene

• BLOC2S1
• DKFZp686F0413
• FLJ22704
• Hermansky-Pudlak syndrome 3
• Hermansky-Pudlak syndrome 3 protein
• HPS3_HUMAN
• SUTAL

Genomic Location

• Decreased immune function (immunodeficiency)
• Involuntary rapid eye movements (nystagmus)
• Partial absent skin coloring (partial albinism)
• Absent color in the eye (ocular albinism)
• Lung scarring that gets worse with time (pulmonary fibrosis)
• Inflammation of the colon (colitis)
• Poor absorption of nutrients (malabsorption)

• Medical geneticist
• Ophthalmologist
• Dermatologist
• Hematologist
• Gastroenterologist
• Pulmonologist

Hermansky-Pudlak syndrome is a rare disorder in most populations and is estimated to affect 1 in 500,000 to 1,000,000 individuals worldwide. Type 1 is more common in Puerto Rico, particularly in the northwestern part of the island where about 1 in 1,800 people are affected. Type 3 is common in people from central Puerto Rico. Groups of affected individuals have been identified in many other regions, including India, Japan, the United Kingdom, and Western Europe.