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DLD
dihydrolipoamide dehydrogenase
The DLD gene provides instructions for making dihydrolipoamide dehydrogenase, an enzyme vital for energy metabolism within cells, participating in several key enzyme complexes. DLD is a gene that codes for dihydrolipoamide dehydrogenase, a critical component of multiple enzyme complexes involved in cellular energy production.
DLD is located on the long (q) arm of chromosome 7, at band 7q31.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The DLD gene encodes the dihydrolipoamide dehydrogenase enzyme, also known as the E3 component. This enzyme is an essential part of several multi-enzyme complexes that play a crucial role in the body's energy-generating pathways. These complexes are involved in breaking down carbohydrates, amino acids, and other molecules to produce adenosine triphosphate (ATP), the primary energy currency of cells.
What the gene does
The dihydrolipoamide dehydrogenase enzyme, produced from the DLD gene, acts as a shared component (the E3 subunit) in at least three major enzyme complexes. These include the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-keto acid dehydrogenase (BCKD) complex, and the alpha-ketoglutarate dehydrogenase (αKGDH) complex. The PDH complex converts pyruvate, derived from carbohydrates, into acetyl-CoA, initiating a series of reactions that generate ATP. The BCKD complex is responsible for breaking down the branched-chain amino acids leucine, isoleucine, and valine, which are obtained from the diet, into molecules that can be used for energy. The αKGDH complex participates in a step that converts alpha-ketoglutarate to succinyl-CoA, also leading to ATP production. Therefore, DLD plays a central role in metabolic pathways crucial for cellular energy supply.
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Chromosome location
The DLD gene is located on chromosome 7, specifically at position 7q31.1. This means it resides on the long arm (q) of chromosome 7, within region 3, band 1, sub-band 1.
Protein structure
The DLD gene encodes a protein that is 509 amino acids long. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the DLD gene can alter the function of the dihydrolipoamide dehydrogenase enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. Such variants may lead to a reduction in enzyme activity or complete loss of function, impacting metabolic processes.
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.1058T>C | p.Ile353Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.1182C>G | p.Tyr394Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.1214C>A | p.Ser405Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.1344_1347del | p.Asp448fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.1464+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.175A>T | p.Lys59Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.285_286del | p.His96fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.405_407del | p.Gly137del | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.821dup | p.Leu274fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 deficiency |
c.82dup | p.Ser28fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3 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 DLD gene are primarily associated with dihydrolipoamide dehydrogenase deficiency. This condition presents with a wide spectrum of symptoms, commonly including lactic acidosis (a build-up of lactic acid), neurological issues, and liver dysfunction. Some DLD variants have also been implicated in Leigh syndrome, a severe neurological disorder.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DLD 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 DLD gene is included in several NHS Genomic Medicine Service national panels, indicating its recognised clinical significance in the UK. It is listed as 'green' on PanelApp for conditions such as Dystonia, chorea or related movement disorder (childhood onset), Intellectual disability, Likely inborn error of metabolism, Mitochondrial disorders, Possible mitochondrial disorder (nuclear genes), Pyruvate dehydrogenase (PDH) deficiency, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the DLD gene?
The DLD gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase. This enzyme is a critical component of several multi-enzyme complexes essential for cellular energy production, breaking down carbohydrates and amino acids.
What conditions are associated with variants in the DLD gene?
Variants in the DLD gene are primarily associated with dihydrolipoamide dehydrogenase deficiency. This condition can lead to a range of symptoms, including lactic acidosis, neurological problems, and liver disease. Some variants may also be linked to Leigh syndrome.
How does the DLD enzyme contribute to energy production?
The DLD enzyme is part of key complexes like pyruvate dehydrogenase, branched-chain alpha-keto acid dehydrogenase, and alpha-ketoglutarate dehydrogenase. These complexes perform steps in metabolic pathways that convert various molecules into forms the cell can use to generate ATP, its main energy source.
References
- Ambrus A, Adam-Vizi V. Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase. Archives of biochemistry and biophysics. 2013. PMID: 24012808
- 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
- Brautigam CA, Chuang JL, Tomchick DR. Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations. Journal of molecular biology. 2005. PMID: 15946682
- Cerna L, Wenchich L, Hansiková H. Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency. Medical science monitor : international medical journal of experimental and clinical research. 2001. PMID: 11687750
- Saada A, Aptowitzer I, Link G. ATP synthesis in lipoamide dehydrogenase deficiency. Biochemical and biophysical research communications. 2000. PMID: 10708561
- Shany E, Saada A, Landau D. Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain. Biochemical and biophysical research communications. 1999. PMID: 10448086
- Shaag A, Saada A, Berger I. Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. American journal of medical genetics. 1999. PMID: 9934985
- Hong YS, Kerr DS, Liu TC. Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del). Analysis of a family and prenatal testing. Biochimica et biophysica acta. 1997. PMID: 9540846
- Feigenbaum AS, Robinson BH. The structure of the human dihydrolipoamide dehydrogenase gene (DLD) and its upstream elements. Genomics. 1993. PMID: 8406489