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DLD
dihydrolipoamide dehydrogenase
The DLD gene provides instructions for making dihydrolipoamide dehydrogenase, an enzyme vital for cellular energy metabolism as a component of several enzyme complexes. The DLD gene is responsible for producing the dihydrolipoamide dehydrogenase enzyme, also known as the E3 component.
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 enzyme dihydrolipoamide dehydrogenase, a crucial component in several multi-enzyme complexes. These complexes are fundamental for breaking down various molecules to produce cellular energy. Conditions associated with pathogenic variants in the DLD gene primarily involve metabolic dysfunction.
What the gene does
The dihydrolipoamide dehydrogenase enzyme, encoded by the DLD gene, functions as a critical subunit (the E3 component) within multiple enzyme complexes essential for energy production. One such complex is branched-chain alpha-keto acid dehydrogenase (BCKD), which is involved in breaking down the amino acids leucine, isoleucine, and valine, obtained from the diet. Another key complex is pyruvate dehydrogenase (PDH), which converts pyruvate (from carbohydrates) into acetyl-CoA, initiating a pathway that generates the cell's main energy source, adenosine triphosphate (ATP). Additionally, dihydrolipoamide dehydrogenase is part of the alpha-ketoglutarate dehydrogenase (αKGDH) complex, which converts α-ketoglutarate to succinyl-CoA, further contributing to ATP production.
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Chromosome location
The DLD gene is located on chromosome 7, specifically at position 7q31.1. This region of the human genome contains the genetic instructions for producing the dihydrolipoamide dehydrogenase enzyme.
Protein structure
The DLD gene codes for 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 may lead to reduced enzyme activity, impairing the body's ability to produce energy effectively. Such variants are typically inherited in an autosomal recessive manner.
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 associated with dihydrolipoamide dehydrogenase deficiency. This condition can manifest with a range of symptoms, including lactic acidosis, neurological issues, and liver disease. Some individuals with DLD variants may also present with Leigh syndrome.
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 recognised within several NHS Genomic Medicine Service national panels in the UK. It is categorised as 'green' in panels such as DDG2P, 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 DLD gene?
The DLD gene provides the instructions for making the dihydrolipoamide dehydrogenase enzyme, which is crucial for cellular energy production. This enzyme is part of several complexes that break down carbohydrates, amino acids, and fats.
What happens if the DLD gene doesn't work correctly?
If the DLD gene has pathogenic variants, the resulting enzyme may not function properly. This can lead to conditions like dihydrolipoamide dehydrogenase deficiency, affecting the body's ability to produce energy and causing symptoms such as lactic acidosis, neurological problems, and liver issues.
How is a DLD gene variant inherited?
Variants in the DLD gene are typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the pathogenic variant, one from each parent, to develop the associated condition.
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