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DLAT
dihydrolipoamide S-acetyltransferase
The DLAT gene provides instructions for making an enzyme called dihydrolipoamide S-acetyltransferase, which is a key component of the pyruvate dehydrogenase complex vital for cellular energy metabolism. DLAT encodes the E2 enzyme, an integral part of the pyruvate dehydrogenase complex (PDC) which plays a central role in converting carbohydrates into usable cellular energy.
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, or dihydrolipoamide S-acetyltransferase, is essential for normal cellular metabolism, particularly in the conversion of nutrients into energy. It codes for a subunit of the pyruvate dehydrogenase complex (PDC), a large enzyme system located in the mitochondria. The PDC is responsible for linking glycolysis to the citric acid cycle, a fundamental process for generating adenosine triphosphate (ATP), the cell's principal energy-carrying molecule.
What the gene does
The DLAT gene directs the synthesis of the E2 enzyme, also known as dihydrolipoamide acetyltransferase. This E2 component forms the core of the multi-enzyme pyruvate dehydrogenase complex (PDC). The PDC is assembled from several copies of three different enzymes, including E2, along with various associated proteins. The E2 enzyme functions as a central scaffold to which other proteins attach, enabling the formation of the complex. The pyruvate dehydrogenase complex is crucial for converting energy from food into a usable form for cells. Specifically, it transforms pyruvate, derived from carbohydrate breakdown, into acetyl-CoA. The E2 enzyme executes a specific step within this chemical transformation. This conversion of pyruvate is an essential initial stage for a series of biochemical reactions that ultimately produce adenosine triphosphate (ATP). Disruptions to this enzyme's function can impair the body's ability to produce energy effectively.
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Chromosome location
The DLAT gene is situated on chromosome 11 at band 11q23.1. This specific genomic location houses the genetic instructions necessary for the synthesis of the dihydrolipoamide S-acetyltransferase enzyme.
Protein structure
The DLAT protein is 647 amino acids in length. Its structure includes several key regions and domains that are critical for its function within the pyruvate dehydrogenase complex. These include a Disordered region (amino acids 29-49), Lipoyl-binding 1 Domain (amino acids 91-167), a second Disordered region (amino acids 184-219), Lipoyl-binding 2 Domain (amino acids 218-294), another Disordered region (amino acids 312-346), and a Peripheral subunit-binding (PSBD) Domain (amino acids 356-393). These domains facilitate the protein's interactions and enzymatic activity.
Key variants
Genetic variations within the DLAT gene can lead to alterations in the structure or function of the dihydrolipoamide S-acetyltransferase enzyme. These changes may impact the efficiency of the pyruvate dehydrogenase complex, potentially disrupting cellular energy production. While DLAT variants are a rare cause of associated conditions, understanding their nature is important for diagnosis.
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
While pathogenic variants in DLAT can cause pyruvate dehydrogenase deficiency, DLAT mutations represent a very uncommon cause of this metabolic disorder. Only a small number of cases have been attributed to DLAT changes, with at least two specific mutations identified. This condition is characterised by a potentially life-threatening buildup of lactic acid in the body. The gene has also been mentioned in medical literature in relation to Leigh syndrome.
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 the NHS Genomic Medicine Service due to its clinical relevance. It is present on several NHS England national genomic test directories, as evidenced by its 'green' status on PanelApp for conditions such as Pyruvate dehydrogenase (PDH) deficiency (R316), Mitochondrial disorders, and Early onset dystonia, indicating that there is strong evidence for its association with these conditions and it is routinely assessed in a clinical setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the DLAT gene?
The DLAT gene provides instructions for creating the E2 enzyme, which is a core component of the pyruvate dehydrogenase complex. This complex is vital for converting pyruvate into acetyl-CoA, a crucial transformation that enables cells to harness energy from carbohydrates.
What health conditions are associated with changes in the DLAT gene?
Variants in the DLAT gene are primarily linked to pyruvate dehydrogenase deficiency, a metabolic disorder that can lead to a buildup of lactic acid, developmental delay, and neurological problems. It has also been noted in some cases of Leigh syndrome.
Is DLAT gene testing available in the UK?
Yes, the DLAT gene is included in several NHS England national genomic test directories, such as for Pyruvate dehydrogenase deficiency. This indicates it is considered clinically relevant and is part of routine genomic testing for specific conditions in the UK.
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