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ACAT1
acetyl-CoA acetyltransferase 1
The ACAT1 gene provides instructions for making an enzyme involved in critical metabolic processes, specifically breaking down proteins and fats to produce energy within cells. The ACAT1 gene is essential for producing the enzyme acetyl-CoA acetyltransferase 1, which 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, also known as acetyl-CoA acetyltransferase 1, is crucial for cellular energy metabolism. It encodes an enzyme that operates within the mitochondria, the cell's powerhouses, to facilitate the breakdown of dietary proteins and fats.
This gene's product helps manage the body's energy supply by converting molecules into forms that can be used for energy generation. Understanding ACAT1's function is important for comprehending inherited metabolic conditions.
What the gene does
The ACAT1 gene directs the synthesis of an enzyme primarily found in the mitochondria, where it plays a key role in metabolic pathways. This enzyme is instrumental in processing specific dietary components, including proteins and fats. It contributes to the breakdown of isoleucine, an amino acid, by converting 2-methyl-acetoacetyl-CoA into propionyl-CoA and acetyl-CoA, which are then used for energy.
Furthermore, the ACAT1 enzyme is involved in the catabolism of ketones, molecules produced when fats are broken down. It carries out the final step in ketolysis, converting acetoacetyl-CoA into two molecules of acetyl-CoA, also utilised for energy production. In the liver, the enzyme can also catalyse the reverse reaction, contributing to ketogenesis, the formation of new ketones.
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Chromosome location
The ACAT1 gene is situated on chromosome 11 at position q22.3. This specific location refers to the long arm (q) of chromosome 11, within region 22, band 3. The precise placement on the chromosome helps in genetic mapping and understanding its genomic context.
Protein structure
The ACAT1 gene codes for a protein consisting of 427 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the ACAT1 gene can influence the enzyme's structure and function. Over 100 different variants have been identified in individuals with beta-ketothiolase deficiency, which can disrupt the enzyme's normal activity or production. These changes can range from single nucleotide alterations to larger deletions or insertions within the gene.
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 linked to beta-ketothiolase deficiency, an inherited metabolic disorder. This condition is characterised by the body's inability to properly break down certain proteins and fats due to a deficient or non-functional ACAT1 enzyme. Affected individuals typically present with symptoms in early childhood, often experiencing ketoacidotic attacks.
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 expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp. It is rated 'green' for its association with conditions such as DDG2P, Ketotic hypoglycaemia, Likely inborn error of metabolism, and Undiagnosed metabolic disorders, indicating strong evidence for its role in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ACAT1 gene?
The ACAT1 gene provides instructions for an enzyme that is vital for breaking down certain proteins and fats within the mitochondria, the energy-producing parts of cells. This process is crucial for generating cellular energy.
Which condition is associated with ACAT1 gene variants?
Variants in the ACAT1 gene are primarily associated with beta-ketothiolase deficiency, an inherited metabolic disorder. This condition impairs the body's ability to process specific amino acids and ketones, leading to metabolic imbalances.
How does the ACAT1 enzyme contribute to energy production?
The ACAT1 enzyme aids energy production by processing isoleucine, an amino acid, and by facilitating the final step in ketone breakdown. It converts these molecules into acetyl-CoA, which can then be utilised in the cellular energy cycle.
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