Griscelli syndrome is an inherited condition characterized by unusually light (hypopigmented) skin and light silvery-gray hair starting in infancy. Researchers have identified three types of this disorder, which are distinguished by their genetic cause and pattern of signs and symptoms.

Griscelli syndrome type 1 involves severe problems with brain function in addition to the distinctive skin and hair coloring. Affected individuals typically have delayed development, intellectual disability, seizures, weak muscle tone (hypotonia), and eye and vision abnormalities. Another condition called Elejalde disease has many of the same signs and symptoms, and some researchers have proposed that Griscelli syndrome type 1 and Elejalde disease are actually the same disorder.

People with Griscelli syndrome type 2 have immune system abnormalities in addition to having hypopigmented skin and hair. Affected individuals are prone to recurrent infections. They also develop an immune condition called hemophagocytic lymphohistiocytosis (HLH), in which the immune system produces too many activated immune cells called T-lymphocytes and macrophages (histiocytes). Overactivity of these cells can damage organs and tissues throughout the body, causing life-threatening complications if the condition is untreated. People with Griscelli syndrome type 2 do not have the neurological abnormalities of type 1.

Unusually light skin and hair coloring are the only features of Griscelli syndrome type 3. People with this form of the disorder do not have neurological abnormalities or immune system problems.

The three types of Griscelli syndrome are caused by mutations in different genes: Type 1 results from mutations in the MYO5A gene, type 2 is caused by mutations in the RAB27A gene, and type 3 results from mutations in the MLPH gene.

The proteins produced from these genes are found in pigment-producing cells called melanocytes. Within these cells, the proteins work together to transport structures called melanosomes. These structures produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color (pigmentation). Melanosomes are formed near the center of melanocytes, but they must be transported to the outer edge of these cells and then transferred into other types of cells to provide normal pigmentation.

Mutations in any of the three genes, MYO5A, RAB27A, or MLPH, impair the normal transport of melanosomes within melanocytes. As a result, these structures clump near the center of melanocytes, trapping melanin within these cells and preventing normal pigmentation of skin and hair. The clumps of pigment, which can be seen in hair shafts when viewed under a microscope, are a hallmark feature of the condition.

In addition to their roles in melanosome transport, the MYO5A and RAB27A genes have functions elsewhere in the body. Specifically, the protein produced from the MYO5A gene transports materials within nerve cells (neurons) that appear to be critical for cell function. The protein produced from the RAB27A gene is found in immune system cells, where it is involved in the release of certain compounds that kill foreign invaders (such as viruses and bacteria). Mutations in these genes impair these critical cell activities, leading to the neurological problems and immune system abnormalities found in Griscelli syndrome types 1 and 2, respectively.

Normal Function

The MLPH gene provides instructions for making a protein called melanophilin. This protein is found in pigment-producing cells called melanocytes, where it helps transport structures called melanosomes. These structures produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color (pigmentation). Melanophilin interacts with proteins produced from the MYO5A and RAB27A genes to form a complex that transports melanosomes to the outer edges of melanocytes. From there, the melanosomes are transferred to other types of cells, where they provide the pigment needed for normal hair, skin, and eye coloring.

Health Conditions Related to Genetic Changes

Griscelli syndrome

At least one mutation in the MLPH gene has been found to cause Griscelli syndrome. This genetic change causes a form of the condition designated type 3, which is characterized by unusually light (hypopigmented) skin and silvery-gray hair. Unlike the other forms of Griscelli syndrome, type 3 does not involve abnormalities of the brain or immune system.

The known MLPH gene mutation changes a single protein building block (amino acid) in the melanophilin protein. Specifically, it replaces the amino acid arginine with the amino acid tryptophan at protein position 35 (written as Arg35Trp or R35W). This mutation reduces the amount of melanophilin produced; the small amount of protein that is produced is unable to form a complex with the proteins made from the MYO5A and RAB27A genes. Without this complex, melanosomes cannot be transported to the edges of melanocytes. Instead, they clump near the center of melanocytes, trapping melanin within these cells and preventing normal pigmentation of skin and hair.

Other Names for This Gene

• exophilin-3
• l(1)-3Rk
• l1Rk3
• MELPH_HUMAN
• Slac-2a
• SLAC2-A
• slp homolog lacking C2 domains a
• synaptotagmin-like protein 2a

Genomic Location

Normal Function

The MYO5A gene provides instructions for making a protein called myosin Va, which is part of a group of proteins called unconventional myosins. These proteins, which have similar structures, each play a role in transporting molecules within cells. Myosins interact with actin, a protein that is important for cell movement and shape. Researchers believe that myosins use long filaments of actin as tracks along which to transport other molecules.

Myosin Va is found in pigment-producing cells called melanocytes, where it helps transport structures called melanosomes. These structures produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color (pigmentation). Myosin Va interacts with proteins produced from the MLPH and RAB27A genes to form a complex that transports melanosomes to the outer edges of melanocytes. From there, the melanosomes are transferred to other types of cells, where they provide the pigment needed for normal hair, skin, and eye coloring.

Myosin Va also plays an important role in nerve cells (neurons) in the brain. Studies suggest that myosin Va transports various proteins and other molecules within neurons. It is also involved in the release of certain substances from these cells (exocytosis). The movement of these materials appears to be critical for normal brain function.

Health Conditions Related to Genetic Changes

Griscelli syndrome

At least two mutations in the MYO5A gene have been found in people with Griscelli syndrome. These mutations cause a form of the condition designated type 1, which is characterized by unusually light (hypopigmented) skin, silvery-gray hair, and neurological abnormalities resulting in delayed development, intellectual disability, and seizures. The known MYO5A gene mutations prevent the production of functional myosin Va. Because the nonfunctional protein cannot form a complex with the proteins made from the MLPH and RAB27A genes, melanosomes cannot be transported to the edges of melanocytes. Instead, these structures clump near the center of melanocytes, trapping melanin within these cells and preventing normal pigmentation of skin and hair. A loss of myosin Va in neurons disrupts the transport of proteins and other molecules within and out of these cells, which likely causes the neurological problems found in Griscelli syndrome type 1.

Other Names for This Gene

• dilute myosin heavy chain, non-muscle
• GS1
• MYH12
• MYO5
• MYO5A_HUMAN
• myosin VA (heavy chain 12, myoxin)
• myosin, heavy polypeptide kinase
• myosin-12
• myosin-Va
• myoxin
• MYR12
• unconventional myosin-Va

Genomic Location

Normal Function

The RAB27A gene provides instructions for making a protein that is involved in a process called vesicle trafficking, which moves proteins and other molecules within cells in sac-like structures called vesicles. Although the Rab27a protein is found in cells and tissues throughout the body, it appears to be most critical in pigment-producing cells called melanocytes and in certain immune system cells.

In melanocytes, the Rab27a protein helps transport structures called melanosomes. These structures produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color (pigmentation). Rab27a interacts with proteins produced from the MLPH and MYO5A genes to form a complex that transports melanosomes to the outer edges of melanocytes. From there, the melanosomes are transferred to other types of cells, where they provide the pigment needed for normal hair, skin, and eye coloring.

The Rab27a protein also plays an important role in immune system cells called T-lymphocytes. These cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection and illness. Specifically, Rab27a is involved in cytotoxic granule exostosis, which is the process by which T-lymphocytes release cell-killing (cytotoxic) compounds to destroy foreign invaders.

Health Conditions Related to Genetic Changes

Griscelli syndrome

At least 24 mutations in the RAB27A gene have been found in people with Griscelli syndrome. These mutations cause a form of the condition designated type 2, which is characterized by unusually light (hypopigmented) skin, silvery-gray hair, and immune system abnormalities. The known mutations either prevent the production of any Rab27a protein or lead to the production of an abnormal or unstable protein that cannot form a complex with the proteins produced from the MLPH and MYO5A genes. A shortage of functional Rab27a protein impairs the normal transport of melanosomes to the edges of melanocytes. Instead, these structures clump near the center of melanocytes, trapping melanin within these cells and preventing normal pigmentation of skin and hair. A loss of Rab27a function in T-lymphocytes impairs cytotoxic granule exocytosis, making people with Griscelli syndrome type 2 prone to recurrent infections.

Through mechanisms that are not well understood, a shortage of Rab27a in immune system cells also leads to a condition called hemophagocytic lymphohistiocytosis (HLH) in people with Griscelli syndrome type 2. This condition triggers the immune system to produce too many activated T-lymphocytes and other immune cells called macrophages (histiocytes). Overactivity of these cells can damage organs and tissues throughout the body, causing life-threatening complications if the condition is untreated.

Other Names for This Gene

• GS2
• GTP-binding protein Ram
• HsT18676
• rab-27
• RAB27
• RAM
• ras-related protein Rab-27A
• RB27A_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Bone marrow transplantation is the most effective treatment and the only possible cure for Griscelli syndrome type 2 (GS2). Immunosuppressive therapies may be used in preparation for transplantation, and to suppress damage to multiple organs caused by hemophagocytic lymphohistiocystosis. Recurrent infections may be minimized with antibacterial and antiviral medications. In addition, avoiding interactions that increase the risk of infection is important.

Griscelli syndrome is a rare condition; its prevalence is unknown. Type 2 appears to be the most common of the three known types.