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ACADVL
acyl-CoA dehydrogenase very long chain
The ACADVL gene provides instructions for making an enzyme called very long-chain acyl-CoA dehydrogenase (VLCAD), which is crucial for metabolising specific types of fatty acids into energy within the body. The ACADVL gene produces a mitochondrial enzyme essential for the breakdown of very long-chain fatty acids.
ACADVL is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACADVL gene encodes for very long-chain acyl-CoA dehydrogenase (VLCAD), an enzyme located in the mitochondria, the energy-producing centres in cells. This enzyme plays a fundamental role in fatty acid oxidation, a metabolic pathway that converts fats into usable energy for the body.
VLCAD is specifically responsible for breaking down very long-chain fatty acids, which are found in both diet and body fat stores. These fatty acids serve as a significant energy source for vital organs such as the heart and muscles. During periods of fasting, VLCAD's function becomes even more critical, as fatty acids become a primary energy supply for the liver and other tissues.
What the gene does
The ACADVL gene's primary function is to direct the synthesis of very long-chain acyl-CoA dehydrogenase (VLCAD). This enzyme is integral to mitochondrial fatty acid oxidation, a multi-step biochemical process that generates energy from lipids. VLCAD initiates the breakdown of very long-chain fatty acids by catalysing the first step in their oxidation pathway.
This catabolic process is particularly important for organs with high energy demands, such as cardiac and skeletal muscle. During states of prolonged fasting or increased energy expenditure, the efficient breakdown of these fatty acids ensures a continuous supply of energy. Impaired VLCAD function can lead to an accumulation of very long-chain fatty acids and a deficiency in energy production, affecting various bodily systems.
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Chromosome location
The ACADVL gene is situated on chromosome 17 at position 13.1 (17p13.1). This chromosomal location specifies where the gene can be found within the human genome. Genes at this location are often subject to research regarding their role in various biological processes and disease states.
Protein structure
The ACADVL gene encodes a protein consisting of 655 amino acids. This protein has a defined domain architecture that reflects its function. It includes a Disordered region spanning amino acids 23-42, which may have regulatory roles or allow for flexibility. The core Catalytic region, from amino acids 41-482, is responsible for the enzymatic activity of breaking down fatty acids. Additionally, a Membrane-anchoring region is present from amino acids 483-516, which is crucial for localising the enzyme to the mitochondrial membrane where its metabolic activity takes place.
Key variants
Genetic changes, known as variants, in the ACADVL gene can alter the normal function of the very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme. These variants can range from single nucleotide changes that modify specific protein building blocks (amino acids) to larger deletions or insertions within the gene. Such alterations can lead to a dysfunctional or absent enzyme, impairing the body's ability to metabolise very long-chain fatty acids effectively.
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.103_112dup | p.Arg38fs | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.104del | p.Pro35fs | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1077_1077+1delinsCAC | - | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1077+2T>A | - | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1077+2T>C | - | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1141_1143del | p.Glu381del | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1145del | p.Lys382fs | Pathogenic | ★★★☆ | not provided |
c.1193_1194insGCA | p.Tyr398Ter | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1194C>A | p.Tyr398Ter | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
c.1313G>A | p.Gly438Glu | Pathogenic | ★★★☆ | Very long chain acyl-CoA dehydrogenase deficiency |
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 ACADVL gene are associated with an inherited metabolic disorder called very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two affected copies of the gene, one from each parent, to develop the condition. VLCADD impairs the body's ability to convert certain fats into energy, which can lead to a range of symptoms affecting multiple organ systems.
- Very long-chain acyl-CoA dehydrogenase deficiency Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ACADVL 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
In the UK, the ACADVL gene is recognised on several NHS Genomic Medicine Service national panels, indicating its clinical significance. It is part of panels for conditions such as Acute rhabdomyolysis (R419), Foetal anomalies (R21), Hyperammonaemia, Likely inborn error of metabolism (R98), Paediatric or syndromic cardiomyopathy (R135), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders, among others. ACADVL is also listed on the DDG2P (Deciphering Developmental Disorders) gene list, highlighting its role in developmental disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ACADVL gene?
The ACADVL gene provides instructions for making the very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which is essential for breaking down very long-chain fatty acids into energy within the mitochondria.
What condition is associated with ACADVL gene variants?
Variants in the ACADVL gene are associated with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), an inherited metabolic disorder that impairs the body's ability to process certain fats into energy.
How is very long-chain acyl-CoA dehydrogenase deficiency inherited?
Very long-chain acyl-CoA dehydrogenase deficiency is inherited in an autosomal recessive pattern, meaning an individual must inherit a disease-causing variant from each parent to develop the condition.
References
- Goetzman ES, Wang Y, He M. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Molecular genetics and metabolism. 2007. PMID: 17374501
- Merritt JL 2nd, Matern D, Vockley J. In vitro characterization and in vivo expression of human very-long chain acyl-CoA dehydrogenase. Molecular genetics and metabolism. 2006. PMID: 16621643
- Spiekerkoetter U, Sun B, Zytkovicz T. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. The Journal of pediatrics. 2003. PMID: 14517516
- Gregersen N, Andresen BS, Corydon MJ. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Human mutation. 2001. PMID: 11524729
- Pons R, Cavadini P, Baratta S. Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency. Pediatric neurology. 2000. PMID: 10738914
- Souri M, Aoyama T, Hoganson G. Very-long-chain acyl-CoA dehydrogenase subunit assembles to the dimer form on mitochondrial inner membrane. FEBS letters. 1998. PMID: 9599005
- Andresen BS, Bross P, Vianey-Saban C. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Human molecular genetics. 1996. PMID: 8845838
- Aoyama T, Souri M, Ushikubo S. Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients. The Journal of clinical investigation. 1995. PMID: 7769092