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HADH
hydroxyacyl-CoA dehydrogenase
The HADH gene provides instructions for an enzyme essential in the body's fatty acid oxidation process, particularly for breaking down medium-chain and short-chain fatty acids into energy. The HADH gene encodes 3-hydroxyacyl-CoA dehydrogenase, an enzyme that plays a critical role in converting specific fats into energy within cellular mitochondria.
HADH is located on the long (q) arm of chromosome 4, at band 4q25. Arm ratio per GRCh38 - banding schematic.
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Overview
The HADH gene, also known as hydroxyacyl-CoA dehydrogenase, is a gene that provides the blueprint for an enzyme involved in the metabolism of fats. This enzyme, called 3-hydroxyacyl-CoA dehydrogenase, is crucial for breaking down certain types of fats into energy. It is particularly important for the body to convert medium-chain and short-chain fatty acids into usable energy, a process known as fatty acid oxidation. This energy production is vital for the normal functioning of several key organs, including the heart, liver, kidneys, muscles, and pancreas.
Disruptions to the HADH gene's function can lead to metabolic challenges, affecting the body's ability to process fats and produce energy efficiently. Such disruptions are typically inherited in an autosomal recessive pattern.
What the gene does
The HADH gene produces the enzyme 3-hydroxyacyl-CoA dehydrogenase, which is localised within the mitochondria, the energy-producing compartments of cells. This enzyme is a key component of the fatty acid oxidation pathway, a multi-step process that metabolises fats to generate energy. Specifically, the 3-hydroxyacyl-CoA dehydrogenase enzyme is responsible for breaking down medium-chain and short-chain fatty acids. These fatty acids are derived from foods like milk and various oils, and also result from the breakdown of larger fatty acids.
Beyond general energy production, the enzyme's activity is critical for producing ketones from these fatty acids. Ketones serve as a primary energy source for the heart and muscles. During periods of fasting or when energy demands are elevated, ketones also become important for the liver and other tissues. In the pancreas, the enzyme's proper function supports the production of insulin, which regulates blood sugar levels, highlighting its broad metabolic importance.
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Chromosome location
The HADH gene is situated on chromosome 4, specifically at position 4q25. This location describes the gene's address within the human genome, indicating its presence on the long arm ('q') of chromosome 4, within region 25.
Protein structure
The HADH gene encodes a protein consisting of 314 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the HADH gene can affect the structure and function of the 3-hydroxyacyl-CoA dehydrogenase enzyme. These genetic changes can lead to an impaired ability to metabolise specific fatty acids, which can have significant metabolic consequences. Identified variants often result in altered protein shape, reducing the enzyme's efficiency or activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.203dup | p.Ile70fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.261+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.587del | p.Ser196fs | Pathogenic/Likely pathogenic/Likely risk allele | ★★☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.706C>T | p.Arg236Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
g.(?_108911089)_(108911240_?)del | - | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
g.(?_108911089)_(108955513_?)del | - | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.64del | p.Ala22fs | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.776_779del | p.Phe259fs | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.854del | p.Pro285fs | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
c.859del | p.His287fs | Pathogenic | ★☆☆☆ | Deficiency of 3-hydroxyacyl-CoA dehydrogenase |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the HADH gene are associated with several metabolic conditions, primarily involving the body's ability to process fats and regulate blood sugar. These conditions include 3-hydroxyacyl-CoA dehydrogenase deficiency, which directly results from the impaired enzyme function. Additionally, HADH gene variants have been linked to congenital hyperinsulinism, a disorder characterised by excessively high insulin levels and dangerously low blood glucose (hypoglycaemia).
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HADH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HADH gene is included in several NHS England Genomic Medicine Service national test panels. It is recognised for its association with conditions such as congenital hyperinsulinism, likely inborn errors of metabolism, and undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the HADH gene?
The HADH gene provides instructions for creating an enzyme called 3-hydroxyacyl-CoA dehydrogenase. This enzyme is crucial for breaking down medium-chain and short-chain fatty acids into energy within the body's cells.
How does the HADH gene affect energy production?
The enzyme produced by the HADH gene functions in mitochondria to convert fats into ketones, which are a primary energy source for organs like the heart and muscles. This process is especially important during fasting or when energy demands are high.
What health conditions are associated with HADH gene variants?
Variants in the HADH gene are associated with 3-hydroxyacyl-CoA dehydrogenase deficiency and congenital hyperinsulinism. These conditions result from the impaired ability to metabolise fatty acids and regulate blood sugar effectively.
References
- Kapoor RR, James C, Flanagan SE. 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19417036
- Bennett MJ, Russell LK, Tokunaga C. Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase. Molecular genetics and metabolism. 2006. PMID: 16725361
- Hussain K, Clayton PT, Krywawych S. Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. The Journal of pediatrics. 2005. PMID: 15870679
- Yang SY, He XY, Schulz H. 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. The FEBS journal. 2005. PMID: 16176262
- Molven A, Matre GE, Duran M. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. 2004. PMID: 14693719
- Clayton PT, Eaton S, Aynsley-Green A. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. The Journal of clinical investigation. 2001. PMID: 11489939