LIAS Gene - Lipoic Acid Synthetase
Essential mitochondrial enzyme for lipoic acid biosynthesis and metabolic regulation
Gene Information Card
| Symbol | LIAS |
|---|---|
| Full Name | Lipoic Acid Synthetase |
| Gene Type | Protein coding |
| Chromosomal Location | 4p14 |
| NCBI Gene ID | 11019 ncbi.nlm.nih.gov/gene/11019 |
| Ensembl ID | ENSG00000121897 |
| UniProt ID | O43766 |
| OMIM ID | 607031 |
| HGNC ID | 16429 |
| Aliases | LAS, LIP1, lipoate synthase, LS, HUSSY-01 |
Description
The LIAS gene encodes lipoic acid synthetase, a mitochondrial iron-sulfur cluster-containing enzyme that catalyzes the final step of de novo lipoic acid biosynthesis. Lipoic acid is an essential cofactor for several key mitochondrial multienzyme complexes, including pyruvate dehydrogenase (PDH), 2-oxoglutarate dehydrogenase (OGDH), branched-chain alpha-keto acid dehydrogenase (BCKDH), and the glycine cleavage system (GCS). LIAS functions by inserting sulfur atoms into the octanoyl moiety to form the dithiolane ring of lipoic acid. Mutations in LIAS cause a rare autosomal recessive disorder characterized by neonatal-onset hyperglycinemia, lactic acidosis, and severe neurological impairment.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| LIAS deficiency (Hyperglycinemia, lactic acidosis, and seizures) | Loss-of-function mutations impair lipoic acid synthesis, leading to deficient activity of lipoate-dependent mitochondrial complexes (PDH, OGDH, BCKDH, GCS), resulting in energy failure, glycine accumulation, and metabolic acidosis. | ClinVar, OMIM |
| Nonketotic hyperglycinemia (NKH) | Defective GCS due to lipoate deficiency causes glycine accumulation in the brain, leading to seizures and encephalopathy. | OMIM, PubMed |
| Mitochondrial encephalopathy | Impaired PDH and OGDH disrupt the TCA cycle and oxidative phosphorylation, causing lactic acidosis and neurological deterioration. | ClinVar, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Kidney | 10.8 | Medium |
| Heart | 9.2 | Medium |
| Brain | 7.1 | Medium |
| Skeletal Muscle | 6.5 | Medium |
| Pancreas | 5.3 | Low |
| Lung | 4.8 | Low |
| Testis | 3.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 11.2 | Hepatocellular carcinoma cell line |
| HEK 293 | 9.8 | Embryonic kidney cells |
| K-562 | 7.5 | Leukemia cell line |
| SH-SY5Y | 6.3 | Neuroblastoma cell line |
| A549 | 5.1 | Lung carcinoma cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.746G>A (p.Arg249His) | Missense | Rare | Loss of function; reduced lipoic acid synthesis |
| c.887G>A (p.Arg296Gln) | Missense | Rare | Loss of function; impaired enzyme activity |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of function; no protein production |
| c.1135C>T (p.Arg379*) | Nonsense | Rare | Loss of function; truncated protein |
Mutation functional classification
Loss of Function (LOF)
Most LIAS mutations are loss-of-function, reducing or abolishing lipoic acid synthetase activity, leading to deficient lipoylation of mitochondrial complexes.
Gain of Function (GOF)
No gain-of-function mutations reported for LIAS.
Dominant Negative (DN)
No dominant-negative mutations reported; LIAS deficiency is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
| • lipoate biosynthetic process (GO:0009107) | • lipoate synthase activity (GO:0016992) |
| • iron ion binding (GO:0005506) | • iron-sulfur cluster binding (GO:0051536) |
| • mitochondrion (GO:0005739) | • catalytic activity (GO:0003824) |
| • metal ion binding (GO:0046872) |
Pathways
• Lipoic acid metabolism (Reactome: R-HSA-6798695)
• Pyruvate metabolism and TCA cycle (Reactome: R-HSA-71406)
• Glycine cleavage complex (Reactome: R-HSA-389661)
• Metabolism of cofactors and vitamins (Reactome: R-HSA-196854)
Protein Summary
Lipoic acid synthetase (UniProt O43766) is a 321-amino acid mitochondrial protein that belongs to the radical SAM (S-adenosylmethionine) superfamily. It contains two [4Fe-4S] clusters essential for its catalytic activity. The enzyme catalyzes the insertion of two sulfur atoms into the octanoyl group attached to the lipoyl carrier protein domains of mitochondrial complexes, forming the dithiolane ring of lipoic acid. This post-translational modification is critical for the function of PDH, OGDH, BCKDH, and GCS. Defects in LIAS lead to a severe metabolic disorder with multi-system involvement.
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