IDH3A: Isocitrate Dehydrogenase 3 (NAD+) Subunit Alpha
Mitochondrial NAD+-dependent isocitrate dehydrogenase catalytic subunit; mutations linked to metabolic and neurological disorders
Gene Information Card
| Symbol | IDH3A |
|---|---|
| Full Name | Isocitrate Dehydrogenase (NAD(+)) 3 Catalytic Subunit Alpha |
| Gene Type | protein-coding |
| Chromosomal Location | 15q25.1 |
| NCBI Gene ID | 3419 ncbi.nlm.nih.gov/gene/3419 |
| Ensembl ID | ENSG00000166444 |
| UniProt ID | P50213 |
| OMIM ID | 601149 |
| HGNC ID | 5384 |
| Aliases | IDH3A, IDH3, IDH3alpha, H-IDH3A |
Description
IDH3A encodes the alpha subunit of the mitochondrial NAD+-dependent isocitrate dehydrogenase (IDH3) complex, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the tricarboxylic acid (TCA) cycle. This heterotetrameric enzyme (2 alpha, 1 beta, 1 gamma) is essential for energy metabolism. Mutations in IDH3A are associated with autosomal recessive retinitis pigmentosa (RP) and early-onset encephalopathy with metabolic disturbances.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Retinitis pigmentosa 90 (RP90) | Loss-of-function mutations impair TCA cycle flux, reducing ATP production in retinal photoreceptors, leading to progressive vision loss. | ClinVar, OMIM #619007 |
| Encephalopathy, progressive, with or without lipodystrophy | Biallelic missense variants disrupt IDH3 activity, causing mitochondrial dysfunction, neurological decline, and metabolic abnormalities. | ClinVar, OMIM #619007 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 28.5 | High |
| Skeletal Muscle | 22.1 | High |
| Kidney | 18.3 | High |
| Liver | 15.7 | Medium |
| Brain | 12.4 | Medium |
| Retina | 11.9 | Medium |
| Lung | 8.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 32.1 | High expression |
| HeLa | 24.5 | High expression |
| K562 | 18.9 | Medium expression |
| HepG2 | 15.3 | Medium expression |
| SH-SY5Y | 12.7 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.260G>A (p.Arg87His) | Missense | <0.01% | Reduced catalytic activity; associated with retinitis pigmentosa |
| c.374C>T (p.Thr125Met) | Missense | <0.01% | Impaired enzyme stability; linked to encephalopathy |
| c.1A>G (p.Met1Val) | Start loss | <0.01% | Loss of protein expression; pathogenic in RP |
Mutation functional classification
Loss of Function (LOF)
Most IDH3A mutations reduce or abolish enzymatic activity, leading to TCA cycle dysfunction and energy deficit in high-demand tissues (retina, brain).
Gain of Function (GOF)
No gain-of-function mutations reported for IDH3A.
Dominant Negative (DN)
No dominant-negative effects described; all known pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
| • isocitrate dehydrogenase (NAD+) activity (GO:0004449) | • tricarboxylic acid cycle (GO:0006099) |
| • mitochondrion (GO:0005739) | • NAD binding (GO:0051287) |
| • catalytic activity (GO:0003824) |
Pathways
• TCA cycle (KEGG: hsa00020)
• Metabolic pathways (KEGG: hsa01100)
• 2-Oxocarboxylic acid metabolism (KEGG: hsa01210)
Protein Summary
IDH3A (UniProt P50213) is a 366-amino acid protein that forms the catalytic core of the mitochondrial NAD+-dependent isocitrate dehydrogenase complex. It contains a mitochondrial transit peptide (residues 1-27) and an isocitrate/isopropylmalate dehydrogenase domain. The protein is highly expressed in tissues with high oxidative metabolism, such as heart, muscle, and retina. Pathogenic missense mutations cluster in the active site and dimer interface, disrupting substrate binding and catalysis.
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