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ACAT1
acetyl-CoA acetyltransferase 1
The ACAT1 gene provides instructions for an enzyme crucial in breaking down proteins and fats, with variants linked to beta-ketothiolase deficiency. The ACAT1 gene encodes acetyl-CoA acetyltransferase 1, an enzyme located in the mitochondria that plays a vital role in cellular energy production.
ACAT1 is located on the long (q) arm of chromosome 11, at band 11q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACAT1 gene, or acetyl-CoA acetyltransferase 1, is essential for metabolic processes within the body. It provides the genetic blueprint for an enzyme primarily found in the mitochondria, the energy-producing powerhouses of cells. This enzyme is critical for the breakdown of dietary proteins and fats, ensuring the body can efficiently convert these macronutrients into usable energy.
Dysfunction of the ACAT1 enzyme due to genetic variants can lead to serious health implications, particularly affecting metabolic pathways. One notable condition associated with ACAT1 variants is beta-ketothiolase deficiency, an inherited metabolic disorder that impacts how the body processes certain molecules.
What the gene does
The ACAT1 gene codes for an enzyme, acetyl-CoA acetyltransferase 1, which performs a key role in mitochondrial metabolism. This enzyme is deeply involved in the catabolism of proteins and fats. Specifically, it helps process isoleucine, an amino acid, by converting 2-methyl-acetoacetyl-CoA into propionyl-CoA and acetyl-CoA, both of which can be utilised for energy generation.
Beyond amino acid metabolism, the ACAT1 enzyme is also critical in ketone body metabolism. It facilitates the final step in ketolysis, the breakdown of ketones, by transforming acetoacetyl-CoA into two molecules of acetyl-CoA for energy production. Conversely, in the liver, this enzyme can catalyse the reverse reaction, contributing to ketogenesis, the process of forming new ketone bodies. This dual function underscores its importance in maintaining metabolic balance.
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Chromosome location
The ACAT1 gene is situated on chromosome 11, specifically at position 11q22.3. This precise location on the long arm (q) of chromosome 11 helps to define its genomic address within the human genome.
Protein structure
The ACAT1 gene produces a protein composed of 427 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variants within the ACAT1 gene can alter the function of the acetyl-CoA acetyltransferase 1 enzyme. More than 100 different pathogenic variants have been identified in individuals with associated conditions. These genetic changes can impair the enzyme's ability to process amino acids and ketones effectively, leading to metabolic disturbances.
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.1006-1G>A | - | Pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1006-1G>C | - | Pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1006-2A>C | - | Pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1032dup | p.Glu345fs | Pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1033_1034del | p.Glu345fs | Pathogenic | ★★☆☆ | not provided |
c.1040T>C | p.Ile347Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1049G>A | p.Trp350Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1114C>T | p.Gln372Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1117A>T | p.Lys373Ter | Pathogenic | ★★☆☆ | Deficiency of acetyl-CoA acetyltransferase |
c.1124A>G | p.Asn375Ser | Pathogenic/Likely pathogenic | ★★☆☆ | ACAT1-related disorder |
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 ACAT1 gene are primarily associated with an inherited metabolic disorder called beta-ketothiolase deficiency. This condition typically manifests early in life, often before the age of two years. It is characterised by episodes, known as ketoacidotic attacks, which can involve severe vomiting, dehydration, and may progress to a coma if not managed appropriately.
Inheritance pattern
Conditions caused by pathogenic ACAT1 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 ACAT1 gene is included in several NHS England Genomic Medicine Service approved panels. It is listed as 'green' on the DDG2P panel, the Ketotic hypoglycaemia panel, and the Undiagnosed metabolic disorders panel, indicating strong evidence for its association with these conditions. It also features on the Likely inborn error of metabolism (R98) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ACAT1 gene?
The ACAT1 gene provides instructions for an enzyme essential for breaking down dietary proteins and fats within the mitochondria. This process helps the body generate energy from amino acids like isoleucine and from ketone bodies.
What health condition is linked to ACAT1 gene variants?
Variants in the ACAT1 gene are primarily associated with beta-ketothiolase deficiency, an inherited metabolic disorder. This condition can lead to ketoacidotic attacks, characterised by vomiting and dehydration, typically appearing in early childhood.
Where is the ACAT1 gene located?
The ACAT1 gene is located on chromosome 11, specifically at the 11q22.3 band. This specifies its position within the human genome.
References
- Grünert SC, Sass JO. 2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways. Orphanet journal of rare diseases. 2020. PMID: 32345314
- Abdelkreem E, Harijan RK, Yamaguchi S. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Human mutation. 2019. PMID: 31268215
- Fukao T, Yamaguchi S, Orii T. Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene. Human mutation. 1995. PMID: 7749408
- Kano M, Fukao T, Yamaguchi S. Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene. Gene. 1991. PMID: 1684944