Hydroxyacyl-Coenzyme A dehydrogenase (HADH) is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

which in humans is encoded by the ''HADH''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Structure

The HADH gene is located on the 4th

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

, with its specific location being identified as 4q22-q26. The gene has 10 exons. The HADH gene encodes a 34.3 kDa protein that has 314 amino acids and 124 observed peptides.

Function

This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its

enzymatic Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

activity is highest with medium-chain-length fatty acids.

Clinical significance

Mutations in this gene cause one form of familial

hyperinsulinemic hypoglycemia Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin ...

. A deficiency is associated with

3-hydroxyacyl-coenzyme A dehydrogenase deficiency 3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. Normally, through a process called fatty acid oxidation, several enzymes work in a ste ...

. Mutations also cause 3-hydroxyacyl-CoA dehydrogenase deficiency. There are a wide variety of mutations that have been identified to cause this disease. Among them are

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

s (A40T, P258L, D57G, Y226H) and

nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...

s (R236X) in the protein, and splicing mutations (261+1G>A, 710-2A>G) and some small deletions (587delC) in the cDNA. One mutation, 636+471G>T in the HADH gene, was shown to create a cryptic splice donor site and an out-of-frame pseudoexon. Most of the described cases have homozygous mutations. This disease has fairly homogenous clinical presentation across cases. The symptoms first appear in early life, between 1.5 hours post birth and 3 years of age, and the most common symptoms are

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

and seizures/convulsions directly related to the hypoglycemia. There are other clinical presentations that have been identified, namely:

myoglobinuria Myoglobinuria is the presence of myoglobin in the urine, which usually results from rhabdomyolysis or muscle injury. Myoglobin is present in muscle cells as a reserve of oxygen. Signs and symptoms Signs and symptoms of myoglobinuria are us ...

, dicarboxylic aciduria, feeding difficulties in infancy, muscular

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

, hepatic

steatosis Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver disea ...

, growth delay, hypertrophic cardiomyopathy, dilated cardiomyopathy, hepatic necrosis, and fulminant hepatic failure. The disorder may be diagnosed by either the analysis of the

molecular genetics Molecular genetics is a sub-field of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the ...

of the individual, or by detection of abnormal metabolite levels in blood and/or plasma. Individuals with this deficiency have an elevated amount of 3-hydroxyglutarate excreted through the urine; a heightened level of C4-OH acylcarnitine in the blood plasma is also a characteristic of this FAO disorder. Most documented cases thus far have shown that individuals are responsive to

diazoxide Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in ...

treatment, and highlight the need for diagnosis and treatment administration as early as possible in order to correct hypoglycemia and avoid irreversible brain damage.

Interactions

HADH has been shown to interact with

Vpr Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for ...

, such that HIV-1 Vpr regulates mitochondrial respiration and enhances the activity of hydroxyacyl-CoA dehydrogenase (HADH) through PPARbeta/delta.

References

External links