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DLAT
dihydrolipoamide S-acetyltransferase
The DLAT gene provides instructions for a key enzyme, dihydrolipoamide S-acetyltransferase (E2), which is an integral part of the pyruvate dehydrogenase complex essential for cellular energy metabolism. DLAT encodes the E2 enzyme, a central component of the pyruvate dehydrogenase complex.
DLAT is located on the long (q) arm of chromosome 11, at band 11q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The DLAT gene, also known as dihydrolipoamide S-acetyltransferase, provides the genetic blueprint for the E2 enzyme. This enzyme is a vital part of the pyruvate dehydrogenase complex (PDC), a large multi-enzyme system located in the mitochondria, the powerhouses of the cell. The PDC is fundamental for cellular respiration, the process by which cells generate energy from food.
Mutations within the DLAT gene can impair the function of the E2 enzyme, leading to a disruption in energy production pathways. This can result in conditions such as pyruvate dehydrogenase deficiency, which affects various body systems, particularly the neurological system.
What the gene does
The DLAT gene directs the synthesis of the dihydrolipoamide S-acetyltransferase (E2) enzyme. This E2 enzyme serves as the core component of the pyruvate dehydrogenase complex (PDC), to which other critical enzymes attach. The PDC is responsible for converting pyruvate, a molecule derived from carbohydrates, into acetyl-CoA.
This conversion is a crucial step that links glycolysis (the breakdown of glucose) to the citric acid cycle (Krebs cycle), the main pathway for generating adenosine triphosphate (ATP), the primary energy currency of the cell. The E2 enzyme specifically catalyses the transfer of an acetyl group from dihydrolipoamide to coenzyme A, forming acetyl-CoA. Without a properly functioning DLAT-encoded E2 enzyme, this essential metabolic step is impaired, impacting the cell's ability to produce energy effectively.
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Chromosome location
The DLAT gene is located on chromosome 11, specifically at position 11q23.1. This means it resides on the long (q) arm of chromosome 11, within region 23, band 1. The precise genomic location helps in understanding its position relative to other genes and in genetic mapping studies.
Protein structure
The DLAT gene encodes a protein that is 647 amino acids long. Its structure includes several distinct functional regions and domains. There are three identified disordered regions: one spanning amino acids 29-49, another from amino acids 184-219, and a third from amino acids 312-346. The protein also contains two Lipoyl-binding domains, with the first located at amino acids 91-167 and the second at amino acids 218-294. Additionally, a Peripheral subunit-binding (PSBD) domain is found between amino acids 356-393, which is important for the assembly of the pyruvate dehydrogenase complex.
Key variants
Genetic variations, or variants, in the DLAT gene can alter the function or production of the E2 enzyme. These variants can range from single nucleotide changes to larger deletions or insertions within the gene sequence. Depending on their nature and location, such variants may reduce the enzyme's activity or stability, leading to an impaired pyruvate dehydrogenase complex function. Most pathogenic variants identified in DLAT are associated with autosomal recessive inheritance patterns.
Sample of pathogenic variants
9 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.1303C>T | p.Arg435Ter | Pathogenic | ★★☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.412G>T | p.Glu138Ter | Pathogenic | ★★☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.848_849del | p.Asp283fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.976-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E2 deficiency |
g.(?_111896197)_(111899689_?)del | - | Pathogenic | ★☆☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.568C>T | p.Gln190Ter | Pathogenic | ★☆☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.723dup | p.Val242fs | Pathogenic | ★☆☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.802del | p.Glu268fs | Pathogenic | ★☆☆☆ | Pyruvate dehydrogenase E2 deficiency |
c.362_364del | p.Glu121del | Pathogenic | - | Pyruvate dehydrogenase E2 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 DLAT gene are primarily associated with pyruvate dehydrogenase deficiency. This condition is characterised by a potentially life-threatening accumulation of lactic acid (lactic acidosis), alongside developmental delay and a range of neurological issues. While DLAT mutations are a rare cause of pyruvate dehydrogenase deficiency, they can lead to significant metabolic dysfunction due to the central role of the E2 enzyme in energy production.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DLAT 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 DLAT gene is recognised within several UK NHS Genomic Medicine Service (GMS) pathways and panels, indicating its clinical relevance in the UK. It is listed as 'green' in DDG2P, a database for developmental disorders. DLAT is also included in panels for conditions such as 'Dystonia, chorea or related movement disorder, childhood onset' (R57), 'Early onset dystonia', 'Likely inborn error of metabolism' (R98), 'Mitochondrial disorders', 'Possible mitochondrial disorder, nuclear genes' (R63), 'Pyruvate dehydrogenase (PDH) deficiency' (R316), 'Structural basal ganglia disorders', and 'Undiagnosed metabolic disorders'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the pyruvate dehydrogenase complex?
The pyruvate dehydrogenase complex (PDC) is a group of enzymes located in the mitochondria that plays a vital role in converting pyruvate into acetyl-CoA. This conversion is a crucial step in cellular respiration, linking carbohydrate metabolism to the energy production cycle of the cell.
How do DLAT gene variants affect health?
Variants in the DLAT gene can impair the function of the E2 enzyme, which is a core component of the pyruvate dehydrogenase complex. This disruption leads to an inability to efficiently convert pyruvate into acetyl-CoA, resulting in metabolic imbalances and energy deficiency, commonly seen in pyruvate dehydrogenase deficiency.
What is autosomal recessive inheritance?
Autosomal recessive inheritance means that an individual must inherit two copies of a pathogenic gene variant, one from each parent, to develop the associated condition. Individuals who inherit only one copy are typically carriers and usually do not show symptoms.
References
- Patel MS, Korotchkina LG, Sidhu S. Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. Journal of molecular catalysis. B, Enzymatic. 2009. PMID: 20160912
- Head RA, Brown RM, Zolkipli Z. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Annals of neurology. 2005. PMID: 16049940
- Adam MP, Bick S, Mirzaa GM. Primary Pyruvate Dehydrogenase Complex Deficiency Overview. 1993. PMID: 34138529