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ACAD9
acyl-CoA dehydrogenase family member 9
The ACAD9 gene provides instructions for an enzyme essential for mitochondrial function, playing a key role in energy production and the breakdown of 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, directs the production of an enzyme primarily found within the mitochondria, the cell's powerhouses. This enzyme plays a crucial role in two fundamental cellular processes: assembling components for energy generation and metabolising certain types of fats. Dysfunctions associated with the ACAD9 gene can lead to a range of health issues, often impacting muscle and heart function due to impaired energy production.
ACAD9 deficiency is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the condition. This gene is classified for carrier screening due to its association with severe inherited metabolic disorders.
What the gene does
The ACAD9 gene provides instructions for creating an enzyme that has dual functions within the mitochondria. One primary role of the ACAD9 enzyme is its involvement in the assembly of Complex I, which is a critical part of the oxidative phosphorylation process. Oxidative phosphorylation is a multi-step pathway responsible for generating most of the cell's energy in the form of adenosine triphosphate (ATP).
Additionally, the ACAD9 enzyme is active in fatty acid oxidation, which is the process where fats are broken down to produce energy. Specifically, it assists in metabolising long-chain fatty acids like palmitate and oleate. These fatty acids are significant energy sources for the heart and muscles, and during periods of fasting, they become an essential energy supply for the liver and other tissues.
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Chromosome location
The ACAD9 gene is located on chromosome 3 at position 3q21.3. This specific location identifies its position on the long arm ('q') of chromosome 3, within region 21, band 3.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ACAD9 gene can alter the function of the acyl-CoA dehydrogenase family member 9 enzyme. Most identified variants involve changes to single protein building blocks, known as amino acids. These changes can affect the enzyme's ability to properly assemble Complex I or to metabolise long-chain fatty acids, leading to varied clinical outcomes.
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
Pathogenic variants in the ACAD9 gene are associated with ACAD9 deficiency. This condition can present with a wide spectrum of severity, often involving symptoms such as muscle weakness (myopathy), heart problems (cardiomyopathy), and intellectual disability. In some cases, ACAD9 variants specifically impair the assembly of mitochondrial Complex I, contributing to mitochondrial complex I deficiency.
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
The ACAD9 gene is included in several NHS Genomic Medicine Service national testing panels, indicating its recognised clinical significance in the UK. These panels cover conditions such as Acute rhabdomyolysis, Foetal anomalies, Intellectual disability, and Mitochondrial disorders, including Mitochondrial disorder with complex I deficiency. It is also part of panels for Paediatric or syndromic cardiomyopathy and Undiagnosed metabolic disorders, confirming its role in diagnosing a range of metabolic and developmental conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ACAD9 gene?
The ACAD9 gene provides instructions for an enzyme found in mitochondria that is crucial for two main processes: assembling Complex I for cellular energy production and metabolising long-chain fatty acids for energy.
How is ACAD9 deficiency inherited?
ACAD9 deficiency is inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the ACAD9 gene, one from each parent, to develop the condition.
What health issues are associated with ACAD9 gene variants?
Variants in the ACAD9 gene are associated with ACAD9 deficiency, which can manifest with symptoms like muscle weakness, heart problems, and intellectual disability. It is also linked to mitochondrial complex I deficiency.
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