HADHB

The HADHB gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondria of several tissues, particularly the heart, liver, muscles, and the part of the eye that detects light and color (the retina).

Mitochondrial trifunctional protein is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissues. Mitochondrial trifunctional protein is essential for converting long-chain fatty acids to the major source of energy used by the heart and muscles. During periods without food (fasting), this energy source is also important for the liver and other tissues.

Mitochondrial trifunctional protein is made up of eight subunits. Four subunits called alpha are produced by the HADHA gene, and four subunits called beta are produced by the HADHB gene. As the name suggests, mitochondrial trifunctional protein performs three functions. It has three enzyme activities that are essential for fatty acid oxidation, which is the multistep process that metabolizes fats and converts them to energy. The beta subunit performs one of the enzyme activities, known as long-chain 3-keto-acyl-coenzyme A thiolase. The alpha subunit carries out the other two enzyme activities.

mitochondrial trifunctional protein deficiency - caused by mutations in the HADHB gene

Researchers have identified at least 20 HADHB gene mutations that reduce all three enzyme activities of mitochondrial trifunctional protein. Most mutations change one of the building blocks (amino acids) used to make the protein's beta subunit. A change in amino acids probably alters the subunit's structure, which disrupts all three activities of the enzyme complex. Some mutations produce abnormally small, unstable beta subunits, which leads to a decreased amount of mitochondrial trifunctional protein.

With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of this disorder, such as lethargy and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.

other disorders - increased risk from variations of the HADHB gene

HADHB mutations appear to increase the risk of two serious liver disorders that can develop in women during pregnancy. These disorders are acute fatty liver of pregnancy, which begins with abdominal pain and can rapidly progress to liver failure, and HELLP syndrome, characterized by the breakdown of red blood cells (hemolysis), elevated liver enzyme levels, and a low number of platelets (the cell fragments involved with blood clotting). A small percentage of women who have a mutation in one copy of the HADHB gene and carry a fetus with mutations in both copies of the HADHB gene develop one of these maternal liver diseases. Little is known about the relationship between HADHB mutations and liver problems in the mother during pregnancy. One possibility is that partially metabolized long-chain fatty acids produced by the fetus or placenta accumulate in the mother and are toxic to the liver.