LIPA

The LIPA gene provides instructions for making an enzyme called lysosomal acid lipase. This enzyme is found in the lysosomes (compartments that digest and recycle materials in the cell), where it breaks down fats (lipids) such as cholesteryl esters and triglycerides.

In the body, cholesterol works with high-density lipoproteins (HDL), often referred to as "good cholesterol." High-density lipoproteins carry cholesterol from the body's tissues to the liver for removal. When the cholesterol is attached to a fatty acid it is a cholesteryl ester. Normally, the cholesteryl esters are broken down by lysosomal acid lipase into cholesterol and a fatty acid and then excreted or used by the body as nutrients.

cholesteryl ester storage disease - caused by mutations in the LIPA gene

More than 20 mutations in the LIPA gene have been found to cause cholesteryl ester storage disease. Most of these mutations change single amino acids in lysosomal acid lipase and decrease the protein's functional ability.

The most common LIPA mutation that causes cholesteryl ester storage disease disrupts how genetic information is spliced together to make the blueprint for producing lysosomal acid lipase. This particular mutation, called a splice-site mutation, substitutes the nucleotide guanine for the nucleotide adenine near an area of the gene called exon 8 (written as IVS8-1G>A). (Nucleotides are the building blocks of DNA.) This mutation disrupts the way the gene's instructions are used to make the enzyme, resulting in a deletion of 24 building blocks of protein (amino acids). People with the IVS8-1G>A mutation in both copies of the LIPA gene in each cell have only 5 percent of the normal amount of liposomal lipase activity.

Decreased lysosomal acid lipase activity leads to an accumulation of cholesteryl esters and triglycerides in the cells and tissues throughout the body, particularly the heart and liver. In general, lower lysosomal acid lipase activity results in more severe disease.

Wolman disease - caused by mutations in the LIPA gene

More than 10 mutations in the LIPA gene have been found to cause Wolman disease. Most of these mutations result in the production of an abnormally short version of lysosomal acid lipase, which does not function properly.

The lack of lysosomal acid lipase activity results in an accumulation of cholesteryl esters and triglycerides in the cells and tissues of the spleen, liver, bone marrow, small intestine, adrenal glands, and lymph nodes. This accumulation as well as malnutrition caused by the body's inability to use lipids properly result in the signs and symptoms of Wolman disease.