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ACAD9
acyl-CoA dehydrogenase family member 9
The ACAD9 gene provides instructions for an enzyme crucial for mitochondrial function, particularly in assembling complex I of the electron transport chain and metabolising long-chain fatty acids. The ACAD9 gene encodes acyl-CoA dehydrogenase family member 9, an enzyme located in the mitochondria.
ACAD9 is located on the long (q) arm of chromosome 3, at band 3q21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACAD9 gene, or acyl-CoA dehydrogenase family member 9, provides the genetic blueprint for an enzyme essential within the mitochondria, the cell's powerhouses. This enzyme is involved in two critical processes for energy generation: the assembly of complex I within the oxidative phosphorylation pathway and the metabolism of long-chain fatty acids.
Disruptions to the ACAD9 gene can lead to ACAD9 deficiency, a condition that can manifest with varying severity, affecting muscle function, heart health, and cognitive development.
What the gene does
The ACAD9 gene produces an enzyme found in mitochondria that performs two primary functions. Firstly, it is critical for the proper assembly of complex I, a large protein complex involved in oxidative phosphorylation. This multi-step process is how cells generate most of their energy.
Secondly, the ACAD9 enzyme is involved in fatty acid oxidation, which is the process of breaking down fats into energy within the mitochondria. Specifically, it helps metabolise long-chain fatty acids, such as palmitate and oleate. These fatty acids serve as a significant energy source for the heart and muscles and become particularly important for the liver and other tissues during periods of fasting.
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Chromosome location
The ACAD9 gene is located on chromosome 3, specifically at position 3q21.3. This chromosomal address helps identify its precise location within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic changes, or variants, within the ACAD9 gene can alter the function of the encoded enzyme. These variants are typically single amino acid substitutions, which can affect the protein's ability to facilitate complex I assembly or fatty acid oxidation. Pathogenic variants can lead to a reduction or loss of enzyme 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.153_156del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Acyl-CoA dehydrogenase 9 deficiency |
c.1029+1dup | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1030-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1060dup | p.Tyr354fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1168G>A | p.Ala390Thr | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1237G>A | p.Glu413Lys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1240C>A | p.Arg414Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Acyl-CoA dehydrogenase 9 deficiency |
c.1240C>T | p.Arg414Cys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1249C>T | p.Arg417Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Acyl-CoA dehydrogenase 9 deficiency |
c.1288_1291dup | p.Ile431fs | Pathogenic/Likely pathogenic | ★★☆☆ | Acyl-CoA dehydrogenase 9 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
Variants in the ACAD9 gene are associated with ACAD9 deficiency. This condition presents with a wide range of symptoms and severity, which can include muscle weakness (myopathy), heart problems (cardiomyopathy), and intellectual disability. These clinical manifestations are largely due to impaired mitochondrial function, particularly issues with complex I assembly.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ACAD9 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
ACAD9 is recognised in the UK by NHS England's Genomic Medicine Service (GMS) for its association with several conditions. It is included on PanelApp Green listings for Acute rhabdomyolysis (R419), DDG2P, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Mitochondrial disorders, Mitochondrial disorder with complex I deficiency (R353), Paediatric or syndromic cardiomyopathy (R135), Possible mitochondrial disorder, nuclear genes (R63), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders. A 'Green' rating indicates there is sufficient evidence to support its inclusion on these panels for diagnostic testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ACAD9 enzyme?
The ACAD9 enzyme, located in the mitochondria, plays two crucial roles: it helps assemble complex I for cellular energy production through oxidative phosphorylation, and it aids in breaking down long-chain fatty acids for energy.
What is ACAD9 deficiency?
ACAD9 deficiency is a condition caused by genetic changes in the ACAD9 gene. It can lead to varied symptoms including muscle weakness, heart problems, and intellectual disability, primarily due to impaired mitochondrial function and energy production.
How does ACAD9 contribute to energy production?
ACAD9 contributes to energy production in two ways: by assisting in the formation of mitochondrial complex I, which is a key component of the electron transport chain, and by metabolising long-chain fatty acids into usable energy.
References
- Schiff M, Haberberger B, Xia C. Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Human molecular genetics. 2015. PMID: 25721401
- Nouws J, Te Brinke H, Nijtmans LG. ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies. Human molecular genetics. 2014. PMID: 24158852
- Garone C, Donati MA, Sacchini M. Mitochondrial encephalomyopathy due to a novel mutation in ACAD9. JAMA neurology. 2013. PMID: 23836383