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ACAD8
acyl-CoA dehydrogenase family member 8
The ACAD8 gene provides instructions for producing the isobutyryl-CoA dehydrogenase enzyme, crucial for breaking down the amino acid valine as part of the body's energy production processes. ACAD8 encodes an enzyme called isobutyryl-CoA dehydrogenase (IBD), which plays a key role in cellular metabolism.
ACAD8 is located on the long (q) arm of chromosome 11, at band 11q25. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACAD8 gene, also known as acyl-CoA dehydrogenase family member 8, is essential for normal metabolic function. It provides the genetic blueprint for an enzyme called isobutyryl-CoA dehydrogenase (IBD), which is located within the mitochondria of cells.
Mitochondria are often referred to as the 'powerhouses' of the cell because they are responsible for generating most of the chemical energy needed to power biochemical reactions. The IBD enzyme's role in breaking down certain components of food is critical for this energy production.
What the gene does
The primary function of the ACAD8 gene is to produce the isobutyryl-CoA dehydrogenase (IBD) enzyme. This enzyme is specifically involved in the catabolism, or breakdown, of proteins obtained from food. More precisely, IBD facilitates the third step in the metabolic pathway for valine, which is one of the branched-chain amino acids.
Within the mitochondria, the IBD enzyme converts a molecule known as isobutyryl-CoA into methacrylyl-CoA. Subsequently, other enzymes continue to process methacrylyl-CoA into substances that cells can utilise for energy. This intricate process ensures that amino acids are efficiently metabolised to support cellular growth and development.
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Chromosome location
The ACAD8 gene is situated on chromosome 11, specifically at position 11q25. This location refers to the long (q) arm of chromosome 11, within region 25. The gene comprises multiple exons, which are the coding segments of the gene that provide instructions for protein synthesis.
Protein structure
The ACAD8 gene codes for a protein consisting of 415 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the ACAD8 gene can affect the function of the isobutyryl-CoA dehydrogenase enzyme. These changes can range from single nucleotide polymorphisms to larger deletions or insertions, potentially impacting the enzyme's ability to properly metabolise valine. The consequences of these variants can vary widely, from no observable effect to significant metabolic disruptions.
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.1129G>A | p.Gly377Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.286G>A | p.Gly96Ser | Pathogenic | ★★☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.2T>C | p.Met1Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.384G>A | p.Met128Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.616C>T | p.Arg206Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.886C>T | p.Arg296Ter | Pathogenic | ★★☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.1000C>T | p.Arg334Cys | Pathogenic | ★☆☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.1092+1G>A | - | Pathogenic | ★☆☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.1092+1G>C | - | Pathogenic | ★☆☆☆ | Deficiency of isobutyryl-CoA dehydrogenase |
c.1176G>T | p.Arg392Ser | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
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
Variants in the ACAD8 gene have been identified as the cause of isobutyryl-CoA dehydrogenase deficiency. This condition arises when the IBD enzyme cannot effectively break down valine, disrupting the normal protein metabolism pathway. While some individuals with this deficiency may experience no symptoms, others can be affected differently.
No disease links recorded for this gene in our reference set.
UK clinical status
ACAD8 is recognised in the UK's NHS Genomic Medicine Service. It is listed on PanelApp for "Likely inborn error of metabolism" (R98, green status) and "Undiagnosed metabolic disorders" (green status), indicating its importance in diagnostic screening for metabolic conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the ACAD8 gene?
The ACAD8 gene provides instructions for making the isobutyryl-CoA dehydrogenase (IBD) enzyme. This enzyme is crucial for breaking down the amino acid valine, which is obtained from dietary proteins, as part of the body's energy production processes.
Where in the cell does the ACAD8 enzyme function?
The isobutyryl-CoA dehydrogenase (IBD) enzyme, produced by the ACAD8 gene, is found in the mitochondria. Mitochondria are cellular organelles responsible for generating most of the energy that cells need to function.
What condition is associated with variants in the ACAD8 gene?
Variants in the ACAD8 gene are linked to isobutyryl-CoA dehydrogenase deficiency. This condition impairs the body's ability to properly metabolise the amino acid valine.
References
- Oglesbee D, He M, Majumder N. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency. Genetics in medicine : official journal of the American College of Medical Genetics. 2007. PMID: 17304052
- Pedersen CB, Bischoff C, Christensen E. Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. Pediatric research. 2006. PMID: 16857760
- Koeberl DD, Young SP, Gregersen NS. Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatric research. 2003. PMID: 12736383
- Nguyen TV, Andresen BS, Corydon TJ. Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans. Molecular genetics and metabolism. 2002. PMID: 12359132
- Roe CR, Cederbaum SD, Roe DS. Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Molecular genetics and metabolism. 1998. PMID: 9889013