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HADHA

HADHA

Reviewed July 2009

What is the official name of the HADHA gene?

The official name of this gene is “hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit.”

HADHA is the gene's official symbol. The HADHA gene is also known by other names, listed below.

Read more about gene names and symbols on the About page.

What is the normal function of the HADHA gene?

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. Mitochondrial trifunctional protein is made of eight parts (subunits). Four alpha subunits are produced from the HADHA gene, and four beta subunits are produced from the HADHB gene. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. The alpha subunits contain two of the enzymes, known as long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 2-enoyl-CoA hydratase. The beta subunits contain the third enzyme. These enzymes are essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

Mitochondrial trifunctional protein is required to metabolize a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in the body's fat tissues. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.

How are changes in the HADHA gene related to health conditions?

long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - caused by mutations in the HADHA gene

Researchers have identified several HADHA gene mutations that cause long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. These mutations decrease the long-chain 3-hydroxyacyl-CoA dehydrogenase enzyme activity of mitochondrial trifunctional protein. (The protein's other enzyme activities remain normal or nearly normal.) Many of the HADHA mutations change one of the protein building blocks (amino acids) used to make the 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 HADHA mutations result in an abnormally short, nonfunctional version of the alpha subunit.

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 some features of LCHAD deficiency, such as lack of energy (lethargy) and low blood sugar (hypoglycemia). Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, muscles, and light-sensitive tissue at the back of the eye (retina). This abnormal buildup causes the other signs and symptoms of LCHAD deficiency.

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

Researchers have identified several HADHA gene mutations that cause mitochondrial trifunctional protein deficiency. These mutations reduce all three enzyme activities of mitochondrial trifunctional protein. Some of these mutations result in abnormally short, nonfunctional alpha subunits and lead to decreased levels 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.

When mitochondrial trifunctional protein activity is lost, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of mitochondrial trifunctional protein deficiency.

other disorders - increased risk from variations of the HADHA gene

In a small number of cases, HADHA mutations appear to increase a woman's risk of developing two serious liver disorders during pregnancy, known as acute fatty liver of pregnancy (AFLP) and HELLP syndrome. AFLP begins with abdominal pain and can rapidly progress to liver failure. HELLP stands for hemolysis (the breakdown of red blood cells), elevated liver enzyme levels, and low platelets (cell fragments involved with blood clotting).

A woman is more likely to have AFLP or HELLP syndrome if she has a mutation in one copy of the HADHA gene and the fetus she carries has two copies of a HADHA mutation, particularly the Glu474Gln mutation. Little is known about the relationship between HADHA 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 her liver. In very rare cases of maternal liver disease, the mother has one copy of an altered HADHA gene and the fetus is not affected. In these cases, the role of the mother's HADHA mutation in liver disease is unclear.

Where is the HADHA gene located?

Cytogenetic Location: 2p23

Molecular Location on chromosome 2: base pairs 26,190,634 to 26,244,725

The HADHA gene is located on the short (p) arm of chromosome 2 at position 23.

The HADHA gene is located on the short (p) arm of chromosome 2 at position 23.

More precisely, the HADHA gene is located from base pair 26,190,634 to base pair 26,244,725 on chromosome 2.

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about HADHA?

You and your healthcare professional may find the following resources about HADHA helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the HADHA gene or gene products?

  • ECHA_HUMAN
  • GBP
  • hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit
  • hydroxyacyl dehydrogenase, subunit A
  • LCEH
  • LCHAD
  • long-chain hydroxyacyl-CoA dehydrogenase
  • mitochondrial trifunctional protein, alpha subunit
  • MTPA

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding HADHA?

acids ; acute ; amino acid ; blood clotting ; breakdown ; cell ; clotting ; CoA ; coenzyme A ; deficiency ; dehydrogenase ; enzyme ; fasting ; fatty acids ; fatty liver ; fetus ; gene ; glutamic acid ; glutamine ; hemolysis ; hypoglycemia ; lethargy ; liver failure ; maternal ; mitochondria ; mutation ; oxidation ; placenta ; platelets ; protein ; retina ; subunit ; syndrome ; tissue ; toxic

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (17 links)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

 
Reviewed: July 2009
Published: July 27, 2015