DLD Gene: Dihydrolipoamide Dehydrogenase
Genetic and Functional Insights into DLD, a Key Enzyme in Energy Metabolism and Its Role in Disease
Gene Information Card
| Symbol | DLD |
|---|---|
| Full Name | Dihydrolipoamide Dehydrogenase |
| Gene Type | Protein coding |
| Chromosomal Location | 7q31.1 |
| NCBI Gene ID | 1738 ncbi.nlm.nih.gov/gene/1738 |
| Ensembl ID | ENSG00000091140 |
| UniProt ID | P09622 |
| OMIM ID | 238331 |
| HGNC ID | 2898 |
| Aliases | E3, LAD, PHE3, DLDD, DLDH, GCSL, LDPD |
Description
The DLD gene encodes dihydrolipoamide dehydrogenase, a flavoprotein enzyme that functions as the E3 component of several mitochondrial multienzyme complexes, including the pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, branched-chain alpha-keto acid dehydrogenase complex, and the glycine cleavage system. This enzyme catalyzes the reoxidation of dihydrolipoamide to lipoamide, using NAD+ as an electron acceptor, and is essential for energy metabolism and amino acid catabolism. Mutations in DLD cause dihydrolipoamide dehydrogenase deficiency (also known as lipoamide dehydrogenase deficiency or E3 deficiency), a rare autosomal recessive disorder with variable clinical presentations including metabolic acidosis, neurological deterioration, and liver dysfunction.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Dihydrolipoamide Dehydrogenase Deficiency | Loss-of-function mutations impair reoxidation of dihydrolipoamide, disrupting multiple mitochondrial dehydrogenase complexes and leading to energy failure and toxic metabolite accumulation. | ClinVar, OMIM |
| Maple Syrup Urine Disease (variant form) | Mutations in DLD cause a variant form of maple syrup urine disease (MSUD type III) due to defective branched-chain alpha-keto acid dehydrogenase complex activity. | OMIM |
| Leigh Syndrome | Some DLD mutations are associated with Leigh syndrome, a severe neurodegenerative disorder, due to impaired pyruvate dehydrogenase complex function. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.3 | Medium |
| Heart | 9.8 | Medium |
| Kidney | 8.5 | Medium |
| Skeletal Muscle | 7.2 | Medium |
| Brain | 6.1 | Low |
| Lung | 4.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 14.5 | Hepatocyte cell line, high expression |
| K-562 | 6.2 | Myelogenous leukemia cell line |
| HeLa | 5.8 | Cervical carcinoma cell line |
| A549 | 4.9 | Lung carcinoma cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.685C>T (p.Arg229Trp) | Missense | Common | Loss of function, reduced enzyme activity |
| c.479G>A (p.Arg160Gln) | Missense | Rare | Loss of function, associated with Leigh syndrome |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of function, no protein production |
| c.1040G>A (p.Arg347His) | Missense | Rare | Dominant negative effect reported in some cases |
Mutation functional classification
Loss of Function (LOF)
Most DLD mutations are loss-of-function, reducing or abolishing enzyme activity, leading to metabolic decompensation.
Gain of Function (GOF)
No gain-of-function mutations have been reported for DLD.
Dominant Negative (DN)
Some missense mutations (e.g., p.Arg347His) may exert a dominant negative effect by interfering with dimerization or complex assembly.
View complete mutation data：
Gene Ontology (GO)
| • dihydrolipoyl dehydrogenase activity (GO:0004148) | • mitochondrion (GO:0005739) |
| • coenzyme A biosynthetic process (GO:0009108) | • pyruvate metabolic process (GO:0006090) |
| • branched-chain amino acid catabolic process (GO:0009083) |
Pathways
• Pyruvate metabolism (KEGG: hsa00620)
• Citrate cycle (TCA cycle) (KEGG: hsa00020)
• Glycine
• serine and threonine metabolism (KEGG: hsa00260)
• Valine
• leucine and isoleucine degradation (KEGG: hsa00280)
Protein Summary
Dihydrolipoamide dehydrogenase (DLD) is a 509-amino acid flavoprotein that forms homodimers and functions as the E3 component of multiple mitochondrial alpha-ketoacid dehydrogenase complexes. The protein contains FAD- and NAD+-binding domains and a redox-active disulfide center. It catalyzes the transfer of electrons from dihydrolipoamide to NAD+, regenerating the oxidized lipoamide cofactor. Defects in DLD lead to accumulation of lactate, alpha-ketoglutarate, and branched-chain amino acids, causing metabolic acidosis and neurological symptoms.
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