Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, commonly known as PLOSL, is a progressive disorder that affects the bones and brain. "Polycystic lipomembranous osteodysplasia" refers to cyst-like bone changes that can be seen on x-rays. "Sclerosing leukoencephalopathy" describes specific changes in the brain that are found in people with this disorder.

The bone abnormalities associated with PLOSL usually become apparent in a person's twenties. In most affected individuals, pain and tenderness in the ankles and feet are the first symptoms of the disease. Several years later, broken bones (fractures) begin to occur frequently, particularly in the bones of the ankles, feet, wrists, and hands. Bone pain and fractures are caused by thinning of the bones (osteoporosis) and cysts in the bones. These abnormalities weaken bones and make them more likely to break.

The brain abnormalities characteristic of PLOSL typically appear in a person's thirties. Personality changes are among the first noticeable problems, followed by a loss of judgment, feelings of intense happiness (euphoria), a loss of inhibition, and poor concentration. These neurologic changes cause significant problems in an affected person's social and family life. As the disease progresses, it causes a severe decline in thinking and reasoning abilities (dementia). Affected people ultimately become unable to walk, speak, or care for themselves. People with this disease usually live only into their thirties or forties.

Variants (also called mutations) in the TREM2 gene or the TYROBP gene can cause PLOSL. The proteins produced from these two genes work together to activate certain kinds of cells. These proteins appear to be particularly important in osteoclasts, which are specialized cells that break down and remove (resorb) bone tissue that is no longer needed. Osteoclasts are involved in bone remodeling, which is a normal process that replaces old bone tissue with new bone. The TREM2 and TYROBP proteins are also critical for the normal function of microglia, which are a type of immune cell in the brain and spinal cord (central nervous system). Although these proteins play essential roles in osteoclasts and microglia, their exact function in these cells is unclear.

Variants in the TREM2 or TYROBP gene disrupt normal bone remodeling and lead to progressive brain abnormalities in people with PLOSL. Researchers believe that the bone changes seen in people with this disorder are related to malfunctioning osteoclasts, which are less able to resorb bone tissue during bone remodeling. In the central nervous system, TREM2 or TYROBP gene variants cause widespread abnormalities of microglia. Researchers are working to determine how these abnormalities lead to the neurological problems associated with PLOSL.

Normal Function

The TREM2 gene provides instructions for making a protein called triggering receptor expressed on myeloid cells 2 (TREM2). As its name suggests, this protein is made in myeloid cells, which are cells produced in bone marrow. The TREM2 protein is found on the cell surface, where it interacts with the protein produced from the TYROBP gene. The TREM2 and TYROBP proteins form a complex that transmits chemical signals to activate the cell.

The TYROBP-TREM2 complex was first identified in the immune system. This complex is involved in the growth and development of several types of immune cells, particularly dendritic cells. The TYROBP-TREM2 complex activates these cells, triggering an inflammatory response to injury or disease.

The TYROBP-TREM2 complex also activates cells in the skeletal system and in the brain and spinal cord (central nervous system). In the skeletal system, the complex is found in osteoclasts, which are specialized cells that break down and remove (resorb) bone tissue that is no longer needed. These cells are involved in bone remodeling, which is a normal process that replaces old bone tissue with new bone.

In the central nervous system, the TYROBP-TREM2 complex appears to play an important role in immune cells called microglia. These cells protect the brain and spinal cord from foreign invaders and remove dead nerve cells and other debris. Although the TYROBP-TREM2 complex plays a critical role in osteoclasts and microglia, its exact function in these cells is unclear

Health Conditions Related to Genetic Changes

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy

Variants (also called mutations) in the TREM2 gene have been identified in people with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (commonly known as PLOSL). Some variants prevent the cell from making any TREM2 proteins, while others result in the production of an abnormally short, nonfunctional version of the protein. Other variants change the structure of the TREM2 protein, preventing it from reaching the cell surface.

Researchers believe that the signs and symptoms of PLOSL are related to defective TYROBP-TREM2 signaling in osteoclasts and microglia. The bone abnormalities seen in people with this disorder are probably related to malfunctioning osteoclasts, which are less able to resorb bone tissue during bone remodeling. In the central nervous system, defective signaling through the TYROBP-TREM2 complex causes widespread abnormalities of microglia. Researchers are working to determine how these abnormalities lead to the neurological problems associated with PLOSL.

Other Names for This Gene

• TREM-2
• TREM2_HUMAN
• Trem2a
• Trem2b
• Trem2c
• triggering receptor expressed on monocytes 2
• triggering receptor expressed on myeloid cells 2a

Genomic Location

Normal Function

The TYROBP gene provides instructions for making the TYRO protein tyrosine kinase binding (TYROBP) protein. This protein is found in a variety of cells that are produced in bone marrow (myeloid cells) and other immune system cells (lymphoid cells). The protein is located on the cell surface, where it helps transmit chemical signals that activate the cell.

The TYROBP protein interacts with several other proteins on the surface of cells. For example, it forms a complex with the protein produced from the TREM2 gene. The TYROBP protein and its partners were first identified in the immune system, where they activate certain cells (such as natural killer cells and dendritic cells) that trigger an inflammatory response to injury or disease.

The TYROBP-TREM2 complex also activates cells in the skeletal system and in the brain and spinal cord (central nervous system). In the skeletal system, the complex is found in osteoclasts, which are specialized cells that break down and remove (resorb) bone tissue that is no longer needed. These cells are involved in bone remodeling, which is a normal process that replaces old bone tissue with new bone.

In the central nervous system, the TYROBP-TREM2 complex appears to play an important role in immune cells called microglia. These cells protect the brain and spinal cord from foreign invaders and remove dead nerve cells and other debris. Although the TYROBP-TREM2 complex plays a critical role in osteoclasts and microglia, its exact function in these cells is unclear.

Health Conditions Related to Genetic Changes

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy

Variants (also called mutations) in the TYROBP gene have been identified in people with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (commonly known as PLOSL). One TYROBP gene variant has been found to cause PLOSL in all affected people of Finnish ancestry. This variant deletes a large portion of the TYROBP gene, which prevents the cell from producing any proteins from this gene. Variants in other populations often result in the production of an abnormally short, nonfunctional version of the protein or prevent the protein from reaching the cell surface.

Researchers believe that the signs and symptoms of PLOSL are related to defective TYROBP-TREM2 signaling in osteoclasts and microglia. The bone abnormalities seen in people with this disorder are probably related to malfunctioning osteoclasts, which are less able to resorb bone tissue during bone remodeling. In the central nervous system, defective signaling through the TYROBP-TREM2 complex causes widespread abnormalities of microglia. Researchers are working to determine how these abnormalities lead to the neurological problems associated with PLOSL.

Other Names for This Gene

• DAP12
• DNAX-activation protein 12
• KAR-associated protein
• KARAP
• killer activating receptor associated protein
• TYOBP_HUMAN

Genomic Location

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

PLOSL is a very rare condition. It was first reported in the Finnish population, where it has an estimated prevalence of 1 to 2 per million people. This condition has also been diagnosed in more than 100 people in the Japanese population. Although affected individuals have been reported worldwide, PLOSL appears to be less common in other countries.