Alternative titles; symbols
HGNC Approved Gene Symbol: ACO2
SNOMEDCT: 782822006;
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:41,469,117-41,528,974 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.2 | Infantile cerebellar-retinal degeneration | 614559 | Autosomal recessive | 3 |
| Optic atrophy 9 | 616289 | Autosomal dominant; Autosomal recessive | 3 |
The ACO2 gene encodes mitochondrial aconitase-2, which is involved in the reversible isomerization of citrate into iso-citrate through the cis-aconitate intermediate as part of the second step of the Krebs cycle (summary by Charif et al., 2021).
Mirel et al. (1998) cloned and characterized the essential iron-dependent metabolic enzyme ACO2. They showed that the ACO2 mRNA is 2.7 kb long and is expressed ubiquitously. They detected multiple isoforms of the ACO2 protein.
Mirel et al. (1998) demonstrated that the ACO2 gene contains 18 translated exons distributed over approximately 35 kb of DNA.
Slaughter et al. (1975) reported that an electrophoretic survey had demonstrated 2 alleles at the ACO2 locus. From the findings in heterozygotes, they concluded that both aconitases are monomeric. Sparkes et al. (1978) assigned the ACO2 gene to chromosome 22 by study of Chinese hamster-human hybrid cells. See also Meera Khan et al. (1978) and Slaughter et al. (1978). From study of human-rodent hybrid clones, Geurts van Kessel et al. (1980) concluded that ACO2 is located between 22q11 and 22q13.
In assays of protein purified from bovine heart mitochondria, Bota and Davies (2002) found that the Lon protease (605490) selectively recognized and degraded the oxidized, hydrophobic form of aconitase after mild oxidative modification. Severe oxidation resulted in aconitase aggregation, making it a poor Lon substrate.
Bulteau et al. (2004) found that aconitase activity can undergo reversible citrate-dependent modulation in response to prooxidants. Frataxin (606829) interacted with aconitase in a citrate-dependent fashion, reduced the level of oxidant-induced inactivation, and converted the inactive [3Fe-4S]1+ enzyme to the active [4Fe-4S]2+ form of the protein. Bulteau et al. (2004) concluded that frataxin is an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation.
Chen et al. (2005) showed that yeast mitochondrial aconitase is essential for mitochondrial DNA maintenance independent of its catalytic activity.
Charif et al. (2021) performed functional analysis of cells from 3 patients with mutations in ACO2, including 1 patient with infantile cerebellar-retinal degeneration (ICRD; 614559) and 2 patients with isolated optic atrophy (OPA9; 616289), 1 dominant and 1 recessive case. Western blot analysis revealed that ACO2 amounts were reduced similarly by half in all 3 mutated ACO2 cell lines. Analysis of patient fibroblasts showed an approximately 50% decrease in mitochondrial aconitase activity in both OPA9 patients, whereas the activity was severely reduced in the ICRD cell line. With citrate as the sole substrate, all 3 cell lines showed a significant reduction in the respiration rate, which was most severe in the ICRD cell line. With the addition of pyruvate, respiration increased, but to a lower level than wildtype, and the further addition of other Krebs cycle intermediates restored normal respiration, suggesting that an adaptation process bypasses the Krebs cycle bottleneck due to the reduced ACO2 activity. Measurements of mtDNA abundance showed a significant reduction of more than 50% in all 3 mutated cell lines compared to control cells, reinforcing the role of ACO2, or its substrates, in the maintenance of the mitochondrial genome.
Infantile Cerebellar-Retinal Degeneration
By homozygosity mapping followed by exome sequencing of 2 families with infantile cerebellar-retinal degeneration (ICRD; 614559), Spiegel et al. (2012) identified a homozygous mutation in the ACO2 gene (S112R; 100850.0001). Patients had a severe neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities. Affected individuals showed profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. The patients developed progressive optic atrophy and retinal degeneration. Brain MRI showed progressive cerebral and cerebellar degeneration. The patients did not have mitochondrial disease stigmata such as increased lactate, and mitochondrial respiratory chain activities were normal; only glutamate oxidation was slightly decreased (63% of normal). In vitro functional expression studies in yeast showed that the mutant protein had decreased function under specific physiologic conditions, namely high-requirement conditions such as respiration and growth on 2-carbon substrates.
In 3 patients from 2 unrelated families with ICRD, Metodiev et al. (2014) identified homozygous or compound heterozygous mutations in the ACO2 gene (100850.0004-100850.0006). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. All mutant proteins failed to completely rescue respiratory growth defects in an aco1 (100880)-deficient yeast strain at 37 degrees Celsius, although there was variation in response to different temperatures. ACO1 activity was also reduced in patient cells.
In a 3-year-old boy of Afro-Caribbean and East Indian ancestry with truncal ataxia, hypotonia, developmental delay, and hearing loss, Sadat et al. (2016) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the ACO2 gene, P712L (100850.0015) and R607C (100850.0016). The mutations segregated with disease in the family and were rare or not found in public variant databases. Analysis of patient fibroblasts showed that ACO2 enzyme activity was less than 20% of that observed in control cells, and there was a deficiency in cellular respiration as well as evidence of mitochondrial DNA depletion, with altered expression of some TCA components and electron transport chain subunits. The observed cellular defects were completely restored with ACO2 gene rescue.
In an 18-year-old male with ICRD, Srivastava et al. (2017) identified compound heterozygosity for 2 mutations in the ACO2 gene (100850.0013 and 100850.0014). The mutations were identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations.
In 2 sibs, born of consanguineous Arab-Bedouin parents, with a modified phenotype of infantile cerebellar-retinal degeneration, including spastic paraplegia, impaired intellectual development, and microcephaly without ophthalmologic findings, Bouwkamp et al. (2018) identified a homozygous missense mutation in the ACO2 gene (F414V; 100850.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. Mitochondrial aconitase activity was reduced in lymphoblastoid cells from the affected sibs.
In 2 sisters with severe optic atrophy and spastic paraplegia, Marelli et al. (2018) identified compound heterozygosity for mutations in the ACO2 gene: the previously reported P712L mutation and a splice variant (100850.0017), which segregated with disease. Analysis of patient fibroblasts showed a 40 to 50% reduction in total aconitase activity; no mtDNA depletion was detected in patient cells.
Sharkia et al. (2019) reported molecular findings in an international cohort of 16 patients with biallelic ACO2 mutations, 8 of whom had previously been reported by Spiegel et al. (2012). Ten patients, including 1 sib pair, were homozygous for the S112R mutation (100850.0001). The other 6 patients, including another sib pair, had compound heterozygous mutations, including 10 novel mutations (2 nonsense and 8 missense; see, e.g., H596R, 100850.0008 and R684W, 100850.0009). The mutations, which were identified by whole-exome sequencing and validated by Sanger sequencing, segregated with the disorder in the families.
In 5 patients from 4 families with ICRD, Blackburn et al. (2020) identified homozygous or compound heterozygous mutations in the ACO2 gene (see, e.g., 100850.0010-100850.0012). Two of the patients (P4 and P5) had previously been described in brief in a large clinical exome sequencing study of Saudi patients (REQ18-2038 and 17-6359, respectively) by Monies et al. (2019).
Optic Atrophy 9
In 2 French brothers with isolated optic atrophy-9 (OPA9; 616289), Metodiev et al. (2014) identified compound heterozygous missense mutations in the ACO2 gene (L74V; 100850.0002 and G661R; 100850.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro studies showed that the mutant proteins were unable to completely rescue respiratory growth defects in an aco1-deficient yeast strain at 37 degrees Celsius.
In 2 brothers with optic atrophy, Kelman et al. (2018) screened a panel of 16 optic atrophy-associated genes and identified compound heterozygosity for the previously reported L74V substitution and a 1-bp duplication at a splice site, which the authors stated was of unknown clinical significance.
In a retrospective chart review of 97 patients who had optic nerve pallor or atrophy, with or without vision loss, who underwent mitochondrial and/or nuclear DNA sequencing, Chen et al. (2019) identified 1 patient with total vision loss who was compound heterozygous for the L74V substitution and another missense variant, E696K, of unknown significance.
In a Hispanic brother and sister with optic atrophy, Gibson et al. (2020) performed exome sequencing and identified compound heterozygosity for missense mutations in the ACO2 gene, V632M (100850.0018) and V163L (100850.0019). Their unaffected mother carried the V632M variant; DNA was unavailable from their father. The V163L variant was present in gnomAD 31 times in heterozygous state; V632M was not found in gnomAD. Both sibs carried variants in other genes associated with recessive ophthalmologic disorders, but none were considered causative.
Charif et al. (2021) screened an international cohort of approximately 1,000 molecularly undiagnosed patients with optic atrophy for mutations in the ACO2 gene, and identified 50 patients with heterozygous mutations (e.g., 100850.0020 and 100850.0021) as well as 11 patients with biallelic mutations. There was no significant difference in distribution of mutation type, with two-thirds of all variants being missense mutations in both groups, and nonsense, frameshift, and splice site mutations comprising the remaining third. Segregation analysis in the dominant cases in which familial DNA was available showed that all affected relatives carried the variant, and also revealed 2 cases in which the mutation arose de novo; however, in the families of 5 probands, some relatives carrying the variant were asymptomatic. Five of the biallelic patients carried the recurrent L74V variant (100850.0002) on 1 of their alleles.
In 8 affected individuals from 2 Arab Muslim families with infantile cerebellar-retinal degeneration (ICRD; 614559), Spiegel et al. (2012) identified a homozygous 336C-G transversion in the ACO2 gene, resulting in a ser112-to-arg (S112R) substitution in a highly conserved residue. The mutation was found by homozygosity mapping followed by exome sequencing. Haplotype analysis indicated a founder effect. Ten parents and 1 healthy sib were heterozygous for the mutation, which was not found in 128 controls. Cellular aconitase activity measured in 2 patients was reduced to about 10% of normal levels. In vitro functional expression studies in yeast showed that the mutant protein had decreased function under specific physiologic conditions, namely high-requirement conditions such as respiration and growth on 2-carbon substrates.
In 2 adult French brothers with optic atrophy-9 (OPA9; 616289), Metodiev et al. (2014) identified compound heterozygous mutations in the ACO2 gene: a c.220C-G transversion, resulting in a leu74-to-val (L74V) substitution, and a c.1981G-A transition (c.1981G-A, NM_001098.2), resulting in a gly661-to-arg (G661R; 100850.0003) substitution. Both substitutions occurred at highly conserved residues. Patient cells showed decreased ACO2 activity (31-66% of controls) and decreased ACO2 protein levels. The mutant proteins were unable to completely rescue respiratory growth defects in an aco1 (100880)-deficient yeast strain at 37 degrees Celsius. ACO1 activity was also reduced in patient cells. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The L74V variant (rs141772938) was found at a low frequency (0.003) in the dbSNP database, whereas G661R was not found in that database.
Gibson et al. (2020) noted that the L74V variant, which had been reported several times in compound heterozygous state in patients with isolated optic atrophy, was observed frequently in gnomAD, with an overall allele frequency of 0.37%. The variant was most common among non-Finnish Europeans (0.65%), with 4 homozygotes.
For discussion of the gly661-to-arg (G661R) mutation in the ACO2 gene that was found in compound heterozygous state in patients with optic atrophy-9 (OPA9; 616289) by Metodiev et al. (2014), see 100850.0002.
In 2 sibs, born of consanguineous Algerian parents, with infantile cerebellar-retinal degeneration (ICRD; 614559), Metodiev et al. (2014) identified a homozygous c.776G-A transition (c.776G-A, NM_001098.2) in the ACO2 gene, resulting in a gly259-to-asp (G259D) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP database.
In a 10-year-old girl with infantile cerebellar-retinal degeneration (ICRD; 614559), Metodiev et al. (2014) identified compound heterozygous mutations in the ACO2 gene: a c.2208G-C transversion, resulting in a lys736-to-asn (K736N) substitution at a highly conserved residue, and a 4-bp deletion (c.2325_2328delGAAG, NM_001098.2; 100850.0006), resulting in a frameshift and premature termination (Lys776AsnfsTer49). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP database. (In the article by Metodiev et al. (2014), one of the mutations was listed as c.2328_2331delGAAG and as c.2325_2328delGAAG; Rotig (2020) confirmed that the correct mutation is c.2325_2328delGAAG.)
For discussion of the 4-bp deletion in the ACO2 gene (c.2325_2328delGAAG) that was found in compound heterozygous state in a patient with infantile cerebellar-retinal degeneration (ICRD; 614559) by Metodiev et al. (2014), see 100850.0005.
In 2 sibs, born of consanguineous Arab-Bedouin parents, with a modified phenotype of infantile cerebellar-retinal degeneration (ICRD; 614559), including spastic paraplegia, impaired intellectual development, and microcephaly without ophthalmologic findings, Bouwkamp et al. (2018) identified a homozygous c.1240T-G transversion in the ACO2 gene, resulting in a phe414-to-val (F414V) substitution at a highly conserved residue. The mutation was found by linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing. The parents and an unaffected sib were heterozygous for the mutation. The mutation was not present in the dbSNP database and had a minor allele frequency of less than 0.001 in the EVS6500, 1000 Genomes Project, and ExAC databases. Mitochondrial aconitase activity was reduced in lymphoblastoid cells from the affected sibs, and the respiratory control ratio and state 3 respiration were reduced in isolated lymphoblastoid mitochondria from both patients.
In 2 sibs (patients E2 and E3), aged 8 and 6 years, with infantile cerebellar-retinal degeneration (ICRD; 614559), Sharkia et al. (2019) identified compound heterozygous variants in the ACO2 gene: a c.1787A-G transition, resulting in a his596-to-arg substitution (H596R), and a c.2050C-T transition, resulting in an arg684-to-trp (R684W; 100850.0009) substitution. The mutations were found by whole-exome sequencing and validated by Sanger sequencing. Familial segregation was confirmed by Sanger sequencing. Both mutations occurred in evolutionarily conserved regions and were predicted to impair substrate binding. The sibs had moderately impaired intellectual development, hypotonia, seizures, and ataxia.
For discussion of the c.2050C-T transition in the ACO2 gene that was found in compound heterozygous state in 2 sibs with infantile cerebellar-retinal degeneration (ICRD; 614559) by Sharkia et al. (2019), see 100850.0008.
In a 26-year-old woman (P3) with infantile cerebellar-retinal degeneration (ICRD; 614559), Blackburn et al. (2020) identified compound heterozygous mutations in the ACO2 gene: a del/ins mutation (c.433-2_433-1delinsCT, NM_001098.2) in intron 3, predicted to result in loss of the exon 4 splice site, and a c.719G-A transition, resulting in a gly240-to-asp (G240D; 100850.0011) substitution at a highly conserved residue. The mutations were identified by whole-exome sequencing. The mother was heterozygous for the del/ins mutation, but the father was unavailable for testing. The G240D variant was rare in the gnomAD database and was predicted to have a destabilizing effect.
For discussion of the c.719G-A transition (c.719G-A, NM_001098.2) in the ACO2 gene, resulting in a gly240-to-asp (G240D) substitution, that was found in compound heterozygous state in a patient with infantile cerebellar-retinal degeneration (ICRD; 614559) by Blackburn et al. (2020), see 100850.0010.
In an 11-year-old girl (P5) with infantile cerebellar-retinal degeneration (ICRD; 614559), Blackburn et al. (2020) identified homozygosity for a 2-bp deletion (c.2338_2339delCA, NM_001098.2), resulting in a frameshift (Gln780ValfsTer63). The mutations were identified by whole-exome sequencing, and the parents were confirmed to be mutation carriers by Sanger sequencing. The mutation occurs in the last amino acid before the ACO2 stop codon and is a predicted stop-loss mutation resulting in inclusion of an additional 62 amino acids. The patient had progressive spastic quadriplegia, seizures, hypotonia, absent visually evoked potentials, and severe developmental delay. This patient was previously described in brief (case 17-6359) in a large clinical exome sequencing study of Saudi patients by Monies et al. (2019).
In an 18-year-old male with infantile cerebellar-retinal degeneration (ICRD; 614559), Srivastava et al. (2017) identified compound heterozygosity for 2 mutations in the ACO2 gene: a 4-bp deletion (c.2328delGGAA, NM_001098) predicted to result in a frameshift and premature termination (Lys776AsnfsTer49), and a c.1091T-C transition resulting in a val364-to-ala (V364A; 100850.0014) substitution at a conserved residue. The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. The mutations were not present in the ExAC and 1000 Genomes Project databases. Functional studies were not performed. Srivastava et al. (2017) noted that the frameshift mutation has also been designated c.2325delTAAG.
For discussion of the c.1091T-C transition (c.1091T-C, NM_001098) in the ACO2 gene, resulting in a val364-to-ala (V364A) substitution, that was found in compound heterozygous state in a patient with cerebellar-retinal degeneration (ICRD; 614559) by Srivastava et al. (2017), see 100850.0013.
In a 3-year-old boy of Afro-Caribbean and East Indian ancestry with truncal ataxia, hypotonia, developmental delay, and hearing loss (ICRD; 614559), Sadat et al. (2016) identified compound heterozygosity for a c.2135C-T transition (c.2135C-T, NM_001098) in exon 17 of the ACO2 gene, resulting in a pro712-to-leu (P712L) substitution, and a c.1819C-T transition in exon 15 of the ACO2 gene, resulting in an arg607-to-cys (R607C; 100850.0016) substitution, both involving highly conserved residues. His unaffected parents were each heterozygous for 1 of the mutations. The P712L variant was present once in the ESP5400 database and 4 times in the ExAC database, with no homozygotes reported, whereas the R607C was not found in either database. Analysis of patient fibroblasts demonstrated an 80% reduction in aconitase enzyme activity compared to control fibroblasts, and mitochondria isolated from patient fibroblasts also showed ACO2 activity that was approximately 20% of control cell activity. Whole-cell aconitase activity was completely restored upon transduction of patient cells with wildtype ACO2. Cellular respiration studies revealed that patient fibroblasts had a significantly lower total respiratory capacity and minimal reserve capacity compared to control cells, operating at 40% less capacity than the maximal respiration rate of control cells. Introduction of wildtype ACO2 into patient fibroblasts completely rescued the cellular respiration defects, indicating that the defects were specific for the observed ACO2 deficiency. In addition, the authors performed qPCR and observed a 50% reduction in mtDNA copy number compared to control cells, and mtDNA levels were restored to control levels with introduction of wildtype ACO2 into patient cells. Western blot analysis of other TCA cycle enzymes and OXPHOS complexes showed increases in the steady-state level of subunits of respiratory chain complex II (SDHA; 600857) and complex III (UQCRC2; 191329), as well as subunits of TCA enzyme succinyl-CoA synthetase (SUCLG1, 611224; SUCLG2, 603922); these increased levels were reduced to normal levels in the rescued cell line, suggesting that these changes were a consequence of ACO2 deficiency.
In 2 sisters with severe optic atrophy and spastic paraplegia, Marelli et al. (2018) identified compound heterozygosity for mutations in the ACO2 gene: the previously reported P712L substitution, and a splice site mutation (c.940+5G-C; 100850.0017) in intron 7 of ACO2. RT-PRC analysis of patient fibroblasts demonstrated in-frame skipping of exon 7. No relevant variants were found in other genes causing isolated or syndromic optic atrophy, and their unaffected parents were each heterozygous for 1 of the ACO2 mutations. Analysis of patient fibroblasts showed a 40 to 50% reduction in total aconitase activity; no mtDNA depletion was detected in patient cells.
For discussion of the c.1819C-T transition (c.1819C-T, NM_001098) in exon 15 of the ACO2 gene, resulting in an arg607-to-cys (R607C) substitution, that was found in compound heterozygous state in a 3-year-old boy of Afro-Caribbean and East Indian ancestry with infantile cerebellar-retinal degeneration (ICRD; 614559) by Sadat et al. (2016), see 100850.0015.
For discussion of the splice site variant (c.940+5G-C) in intron 7 of the ACO2 gene, causing in-frame skipping of exon 7, that was found in compound heterozygous state in 2 sisters with severe optic atrophy and spastic paraplegia (ICRD; 614559) by Marelli et al. (2018), see 100850.0015.
In a Hispanic brother and sister with optic atrophy (OPA9; 616289), Gibson et al. (2020) identified compound heterozygosity for missense mutations in the ACO2 gene: a c.1894G-A transition (c.1894G-A, NM_001098.3), resulting in a val632-to-met (V632M) substitution, and a c.487G-T transversion, resulting in a val163-to-leu (V163L; 100850.0019). Both substitutions altered conserved residues. The unaffected mother carried the V632M variant; DNA was unavailable from the father. The V163L variant was present in gnomAD 31 times in heterozygous state; V632M was not found in gnomAD. Functional studies were not reported. Both sibs carried variants in other genes associated with recessive ophthalmologic disorders, but none were considered causative.
For discussion of the c.487G-T transversion (c.487G-T, NM_001098.3) in the ACO2 gene, resulting in a val163-to-leu (V163L) substitution, that was found in compound heterozygous state in a Hispanic brother and sister with optic atrophy (OPA9; 616289) by Gibson et al. (2020), see 100850.0018.
In 4 unrelated probands (P41 to P44) with optic atrophy (OPA9; 616289), Charif et al. (2021) identified heterozygosity for a c.2012G-A transition (c.2012G-A, NM_001098.2) in the ACO2 gene, resulting in an arg671-to-gln (R671Q) substitution. The variant segregated with disease in 2 of the families; DNA was unavailable in the other 2 families. The variant was present in gnomAD at low minor allele frequency (8.01 x 10(-6)). The patients, who ranged in age from 22 years to 61 years, were all diagnosed in childhood; visual acuities ranged from 20/25 to 20/200. All showed central scotoma with optic nerve atrophy, which was diffuse in 2 patients and temporal in 2.
In a 21-year-old woman (P15) with isolated optic atrophy (OPA9; 616289), Charif et al. (2021) identified heterozygosity for a de novo 1-bp duplication (c.1254dupA, NM_001098.2), causing a frameshift predicted to result in a premature termination codon (Gly419fsTer10). The variant was not found in her unaffected parents or in the gnomAD database. Western blot showed that ACO2 expression was reduced by 50% in patient cells. Studies in patient fibroblasts showed a 50% decrease in mitochondrial aconitase activity, as well as a significant reduction in the respiration rate with citrate as the sole substrate. With the addition of pyruvate, respiration increased, but to a lower level than wildtype, and the further addition of other Krebs cycle intermediates restored normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. In addition, mtDNA abundance was reduced more than 50% in patient cells compared to control cells.
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