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ACADVL
acyl-CoA dehydrogenase very long chain
The ACADVL gene provides instructions for producing the very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which plays a crucial role in cellular energy production. The ACADVL gene encodes an enzyme called very long-chain acyl-CoA dehydrogenase (VLCAD).
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 is responsible for producing the very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, a protein critical for metabolic function. This enzyme operates within the mitochondria, often referred to as the 'powerhouses' of cells, where it converts specific fats into usable energy. This process, known as fatty acid oxidation, is particularly important for organs such as the heart and muscles, and during periods of fasting when the body relies heavily on fat stores for energy.
What the gene does
The VLCAD enzyme, encoded by the ACADVL gene, is essential for fatty acid oxidation, a multi-step process that metabolises fats into energy. Specifically, VLCAD facilitates the breakdown of very long-chain fatty acids, which are found in both food and body fat. These fatty acids serve as a significant energy source for the heart and muscles. During periods without food, such as fasting, the liver and other tissues also depend on fatty acids as a key energy supply. Proper function of the VLCAD enzyme ensures that these fats can be efficiently processed to meet the body's energy demands.
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Chromosome location
The ACADVL gene is situated on chromosome 17, specifically at band 17p13.1. This genomic location defines where the gene resides within the human genome, providing a precise address for its genetic material.
Protein structure
The ACADVL gene produces a protein composed of 655 amino acids. The protein's functional architecture includes several key regions. An initial Disordered region is found between amino acids 23 and 42. Following this is a large Catalytic region, spanning amino acids 41 to 482, which is responsible for the enzyme's metabolic activity. Finally, a Membrane-anchoring region from amino acids 483 to 516 helps to situate the enzyme within the mitochondrial membrane.
Key variants
Variants within the ACADVL gene can alter the production or function of the VLCAD enzyme. These genetic changes can range from single amino acid substitutions to deletions of genetic material or the introduction of premature stop signals, all of which can lead to a non-functional or deficient enzyme.
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 known to cause Very long-chain acyl-CoA dehydrogenase deficiency. This is an inherited metabolic disorder where the body is unable to properly break down very long-chain fatty acids, leading to an energy deficit and the accumulation of these fats in tissues.
- 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
The ACADVL gene is recognised in the UK's NHS Genomic Medicine Service, featuring on several PanelApp panels. These include 'Acute rhabdomyolysis', 'DDG2P', 'Foetal anomalies', 'Hyperammonaemia', 'Likely inborn error of metabolism', 'Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies', 'Paediatric or syndromic cardiomyopathy', 'Rhabdomyolysis and metabolic muscle disorders', and 'Undiagnosed metabolic disorders', all categorised as having green evidence ratings.
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. This enzyme is crucial for breaking down very long-chain fatty acids into energy within the mitochondria of cells.
What condition is associated with ACADVL gene variants?
Variants in the ACADVL gene are known to cause Very long-chain acyl-CoA dehydrogenase deficiency. This condition impairs the body's ability to metabolise specific fats for energy.
Why is fatty acid oxidation important?
Fatty acid oxidation is important because it converts fats into usable energy, which is essential for the function of organs like the heart and muscles. It also provides a vital energy source during periods of fasting.
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