ACO2 Gene - Aconitase 2
Mitochondrial Aconitase: Function, Mutations, and Disease Associations
Gene Information Card
| Symbol | ACO2 |
|---|---|
| Full Name | aconitase 2 |
| Gene Type | protein-coding |
| Chromosomal Location | 22q13.2 |
| NCBI Gene ID | 50 ncbi.nlm.nih.gov/gene/50 |
| Ensembl ID | ENSG00000100412 |
| UniProt ID | Q99798 |
| OMIM ID | 100850 |
| HGNC ID | 118 |
| Aliases | ACONM, HEL-S-284, ICRD, MGC14925 |
Description
The ACO2 gene encodes mitochondrial aconitase (aconitate hydratase), an enzyme that catalyzes the reversible conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle. This iron-sulfur cluster-containing protein is essential for cellular energy metabolism. Mutations in ACO2 cause infantile cerebellar-retinal degeneration (ICRD), a severe neurodegenerative disorder. The gene is also implicated in various cancers and metabolic conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Infantile cerebellar-retinal degeneration (ICRD) | Loss-of-function mutations impair TCA cycle flux, leading to mitochondrial dysfunction and neurodegeneration. | OMIM #614559; ClinVar |
| Hereditary spastic paraplegia (HSP) | Missense variants disrupt aconitase activity, causing axonal degeneration. | ClinVar; PubMed |
| Cancer (multiple types) | Altered ACO2 expression and mutations affect cellular metabolism and oxidative stress, promoting tumorigenesis. | COSMIC; PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 28.5 | High |
| Skeletal muscle | 24.3 | High |
| Liver | 18.7 | Medium |
| Brain | 15.2 | Medium |
| Kidney | 14.1 | Medium |
| Lung | 9.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 22.1 | Embryonic kidney cells |
| HeLa | 19.4 | Cervical cancer cells |
| K562 | 16.7 | Leukemia cells |
| HepG2 | 15.3 | Liver cancer cells |
| SH-SY5Y | 12.8 | Neuroblastoma cells |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.184C>T (p.Arg62Trp) | Missense | Rare | Reduced aconitase activity; associated with ICRD |
| c.385G>A (p.Gly129Arg) | Missense | Rare | Impaired iron-sulfur cluster binding; linked to HSP |
| c.1240C>T (p.Arg414Cys) | Missense | Rare | Loss of enzymatic function; ICRD phenotype |
| c.1465G>A (p.Glu489Lys) | Missense | Rare | Decreased protein stability; reported in COSMIC |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic ACO2 mutations are loss-of-function, reducing or abolishing aconitase activity, leading to TCA cycle disruption and mitochondrial dysfunction.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported for ACO2.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by interfering with dimerization or iron-sulfur cluster assembly, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • GO:0003994 - aconitate hydratase activity | • GO:0006099 - tricarboxylic acid cycle |
| • GO:0005739 - mitochondrion | • GO:0006879 - cellular iron ion homeostasis |
| • GO:0051536 - iron-sulfur cluster binding | • GO:0005515 - protein binding |
Pathways
• Tricarboxylic acid cycle (KEGG: hsa00020)
• Carbon metabolism (KEGG: hsa01200)
• 2-Oxocarboxylic acid metabolism (KEGG: hsa01210)
• Metabolic pathways (KEGG: hsa01100)
Protein Summary
Aconitase 2 (ACO2) is a mitochondrial enzyme that catalyzes the stereospecific isomerization of citrate to isocitrate via cis-aconitate in the TCA cycle. The protein contains a [4Fe-4S] iron-sulfur cluster essential for catalytic activity. It exists as a monomer and is highly conserved across species. Defects in ACO2 lead to metabolic and neurodegenerative diseases.
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