HADHA Gene

The official name of HADHA gene is hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit. The HADHA 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).

Function:

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 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 alpha subunit performs two of the enzyme activities, known as long-chain 3-hydroxyacyl-coenzyme A dehydrogenase and long-chain 2-enoyl-coenzyme A hydratase. The beta subunit carries out the third enzyme activity.

Location:

HADHA gene is present in human chromosome 2 and its coded from region 26267008 to 26321098 base pairs with 20 exons, the cytogenetic location 2p23.

Disease

Mutations in this gene causes long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency(LCAD defiency) and Mitochondrial trifunctional protein deficiency

In LCAD defiency Researchers have identified several HADHA gene mutations that decrease the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase enzyme activity of the mitochondrial trifunctional protein. (The protein's other enzyme activities remain normal or near normal.) Many of the HADHA mutations change one of the building blocks (amino acids) used to make the protein's alpha subunit. The most common mutation replaces the amino acid glutamic acid with the amino acid glutamine at position 474 in the alpha subunit. This mutation is written as Glu474Gln or E474Q. The Glu474Gln mutation and other amino acid replacements probably alter the structure of the alpha subunit, preventing it from functioning normally. Other types of HADHA mutations produce an abnormally small, unstable alpha subunit, which is unable to function. With a shortage (deficiency) of functional alpha subunits, 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 long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, such as lack of energy (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 retina, causing more serious complications.

In mitochondrial trifunctional protein deficiency Researchers have identified several HADHA gene mutations that reduce all three enzyme activities of the mitochondrial trifunctional protein. Some mutations produce abnormally small, unstable alpha subunits, which leads to a decreased level of mitochondrial trifunctional protein. Other mutations replace one amino acid with another amino acid in the alpha subunit, which probably alters the subunit's structure and disrupts all three functions of the enzyme complex. 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.