Alternative titles; symbols
HGNC Approved Gene Symbol: IDH3A
Cytogenetic location: 15q25.1 Genomic coordinates (GRCh38): 15:78,149,362-78,171,945 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q25.1 | Retinitis pigmentosa 90 | 619007 | Autosomal recessive | 3 |
Isocitrate dehydrogenases (EC 1.1.1.41 and EC 1.1.1.42) catalyze the oxidative decarboxylation of isocitrate into alpha-ketoglutarate. Thus, they are key enzymes in the tricarboxylic acid (TCA) cycle. In mammalian tissues, 3 kinds of isoenzymes exist, cytosolic NADP(+)-specific IDH (147700), mitochondrial NADP(+)-specific IDH (147650), and mitochondrial NAD(+)-specific IDH (IDH3). Among the mammalian IDH isoenzymes, IDH3 is thought to play a major role in isocitrate decarboxylation in the TCA cycle, since its activity is regulated by numerous allosteric regulators. IDH3, purified to homogeneity from pig heart, is a heterotetramer of the 2-alpha, 1-beta, and 1-gamma subunits, while NADP(+)-specific IDH found in either mitochondria or cytosol is a homodimer (summary by Kim et al., 1995).
Kim et al. (1995) isolated and characterized the cDNA for the alpha subunit of NAD(+)-specific IDH3 (IDH3A), which encodes a mature protein of 339 amino acids (36,640 Da). The human IDH3A sequence showed 44% and 30% amino acid identity to the monkey IDH3G (602017) and bovine IDH2 (147650) gene products, respectively.
By segregation analysis of human biochemical markers and chromosomes in human-mouse somatic cell hybrids, Grzeschik (1976) mapped the ICDM gene to chromosome 15.
By FISH, Huh et al. (1996) mapped the IDH3A gene to chromosome 15q25.1-q25.2.
Retinitis Pigmentosa 90
In 7 patients from 4 unrelated families with retinitis pigmentosa (RP90; 619007), Pierrache et al. (2017) identified homozygosity or compound heterozygosity for mutations in the IDH3A gene (601149.0001-601149.0007). The mutations segregated fully with disease in each family.
In a 7-year-old Chinese boy with RP, Sun and Zhang (2018) identified homozygosity for a missense mutation in the IDH3A gene (M204I; 601149.0008).
In a 54-year-old man from Bosnia Herzegovina with RP, Peter et al. (2019) identified homozygosity for a missense mutation in the IDH3A gene (A122T; 601149.0009).
Associations Pending Confirmation
For discussion of a possible association between developmental and epileptic encephalopathy (see 308350) and variation in the IDH3A gene, see 601149.0001.
While screening for N-ethyl-N-nitrosourea (ENU)-induced recessive mutations with an age-dependent phenotype, Findlay et al. (2018) identified a mouse line that exhibited loss of vision and retinal degeneration associated with increasing age. Affected mice showed a diminished response to a moving visual stimulus at 12 months of age, and the reduced response was maintained at 18 months. Fundal imaging showed retinal degeneration. Genotyping of affected littermates revealed a single common region of homozygosity on chromosome 9, and whole-genome sequencing of the founder male identified an E229K missense mutation in the Idh3a gene that was present in the mutant line. Mice homozygous for the E229K mutation exhibited signs of retinal stress as early as 3 months, but no other tissues appeared to be affected. The authors generated a knockout of Idh3a and found that homozygous mice do not survive past early embryogenesis. Idh3a -/E229K compound heterozygous mutants exhibited more severe retinal degeneration than Idh3a E229K/E229K homozygous mutants. Analysis of mitochondrial function in mutant cell lines demonstrated a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3a E229K/E229K and Idh3a -/E229K cells. Noting that the retina operates with a limited mitochondrial reserve capacity, the authors suggested that this, in combination with the reduced reserve capacity in mutants, explained the degenerative phenotype observed in Idh3a mutant mice.
Retinitis Pigmentosa 90
In an Israeli brother and sister (family B) with retinitis pigmentosa (RP90; 619007), Pierrache et al. (2017) identified compound heterozygosity for mutations in the IDH3A gene: a c.911C-A transversion (c.911C-A, NM_005530.2) resulting in a pro304-to-his (P304H) substitution, and a c.938T-C transition, resulting in a met313-to-thr (M313T; 601149.0002) substitution. Both substitutions involved conserved residues within the mitochondrial NAD-dependent IDH domain, and both were present in the ExAC database, at an allele frequency of 0.0008% and 0.02%, respectively. Their unaffected parents were each heterozygous for 1 of the mutations.
Associations Pending Confirmation
In a 17-month-old boy of North African-Jewish ancestry with severe encephalopathy and intractable seizures (see 308350), Fattal-Valevski et al. (2017) identified homozygosity for a c.911G-T transversion in the IDH3A gene, resulting in a pro304-to-his (P304H) substitution at a highly conserved residue. His unaffected parents were heterozygous for the mutation, which was not found in an in-house database of 1,800 exomes; however, the mutation was present in 5 of 126,200 individuals in the gnomAD database. Functional analysis in yeast demonstrated that, in contrast to wildtype IDH3A, the P304H mutant did not complement IDH-deficient yeast strains for growth on ethanol-acetate. The patient was apneic and bradycardic at birth; examination revealed hypotonia, lethargy, reduced deep tendon reflexes, and absent neonatal reflexes. The hypotonia and hyporeflexia persisted and signs of bulbar involvement appeared, including swallowing difficulties, excessive salivation, absent gag reflex, and central apneic episodes. In addition, there were signs of autonomic dysregulation, with episodes of tachycardia, flushing, and cutis marmorata. Fundoscopic examination at 8 months revealed retinitis pigmentosa and bilateral optic atrophy. The proband exhibited movements suggestive of tonic seizures, and electroencephalography was consistently abnormal, showing a burst-suppression pattern immediately after birth, immaturity of background without epileptiform activity at 3 months, hypsarrhythmia at 5 months, and frequent occipital epileptic activity with asynchronous periodicity at 1 year of age. Brainstem evoked response test indicated profound bilateral sensorineural hearing loss. Due to feeding difficulties and complete dependence on mechanical ventilation, the patient underwent tracheostomy and gastrostomy tube insertion. At 10 months of age, he was discharged with home ventilation, and at age 17 months, his condition remained unchanged.
For discussion of the c.938T-C transition (c.938T-C, NM_005530.2) in the IDH3A gene, resulting in a met313-to-thr (M313T) substitution, that was found in compound heterozygous state in an Israeli brother and sister (family B) with retinitis pigmentosa (RP90; 619007) by Pierrache et al. (2017), see 601149.0001.
In a Dutch sister and brother (family A) with retinitis pigmentosa (RP90; 619007), Pierrache et al. (2017) identified compound heterozygosity for mutations in the IDH3A gene: a c.716T-C transition (c.716T-C, NM_005530.2) resulting in a met239-to-thr (M239T) substitution at a conserved residue within the mitochondrial NAD-dependent IDH domain, and a 1-bp deletion (c.403del; 601149.0004), causing a frameshift predicted to result in a premature termination codon (Thr135fsTer). Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in ExAC database.
For discussion of the 1-bp deletion (c.403del, NM_005530.2) in the IDH3A gene, causing a frameshift predicted to result in a premature termination codon (Thr135fsTer), that was found in compound heterozygous state in a Dutch sister and brother (family A) with retinitis pigmentosa (RP90; 619007) by Pierrache et al. (2017), see 601149.0003.
In a Dutch woman (family C) with retinitis pigmentosa (RP90; 619007), Pierrache et al. (2017) identified homozygosity for a c.524C-T transition (c.524C-T, NM_005530.2) in the IDH3A gene, resulting in an ala175-to-val (A175V) substitution at a conserved residue within the mitochondrial NAD-dependent IDH domain. Her consanguineous unaffected parents were heterozygous for the mutation, which was present in the ExAC database at an allele frequency of 0.0008%.
In 2 South African sisters (family D) with retinitis pigmentosa (RP90; 619007), Pierrache et al. (2017) identified compound heterozygosity for a c.463G-T transversion (c.463G-T, NM_005530.2) in the IDH3A gene, resulting in a gly155-to-ter (G155X) substitution, and a c.946C-T transition, resulting in an arg316-to-cys (R316C; 601149.0007) substitution at a conserved residue within the mitochondrial NAD-dependent IDH domain. Their unaffected mother was heterozygous for the missense variant; DNA results were not reported for their unaffected father. The R316C variant was present at an allele frequency of 0.0008 in the EXaC database.
For discussion of the c.946C-T transition (c.946C-T, NM_005530.2) in the IDH3A gene, resulting in an arg316-to-cys (R316C) substitution, that was found in compound heterozygous state in 2 South African sisters (family D) with retinitis pigmentosa (RP90; 619007) by Pierrache et al. (2017), see 601149.0006.
In a 7-year-old Chinese boy with retinitis pigmentosa (RP90; 619007), Sun and Zhang (2018) identified homozygosity for a c.612G-A transition in exon 7 of the IDH3A gene, resulting in a met204-to-ile (M204I) substitution. The mutation was not found in 3,279 unrelated in-house whole-exome samples or in the ExAC database. Familial segregation was not reported.
In a 54-year-old man from Bosnia Herzegovina (patient 102150L96) with retinitis pigmentosa (RP90; 619007), Peter et al. (2019) identified homozygosity for a c.364G-A transition (c.364G-A, NM_005530.2) in exon 5 of the IDH3A gene, resulting in an ala122-to-thr (A122T) substitution at a highly conserved residue. The mutation was not found in more than 500 unrelated individuals of an internal control cohort, and was present only once in heterozygosity in the gnomAD database. Familial segregation was not reported.
Fattal-Valevski, A., Eliyahu, H., Fraenkel, N. D., Elmaliach, G., Hausman-Kedem, M., Shaag, A., Mandel, D., Pines, O., Elpeleg, O. Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy. Neurogenetics 18: 57-61, 2017. [PubMed: 28058510] [Full Text: https://doi.org/10.1007/s10048-016-0507-z]
Findlay, A. S., Carter, R. N., Starbuck, B., McKie, L., Novakova, K., Budd, P. S., Keighren, M. A., Marsh, J. A., Cross, S. H., Simon, M. M., Potter, P. K., Morton, N. M., Jackson, I. J. Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function. Dis. Model. Mech. 11: dmm036426, 2018. Note: Electronic Article. [PubMed: 30478029] [Full Text: https://doi.org/10.1242/dmm.036426]
Grzeschik, K.-H. Assignment of a gene for human mitochondrial isocitrate dehydrogenase (ICD-M, EC 1.1.1.41.) to chromosome 15. Hum. Genet. 34: 23-28, 1976. [PubMed: 965003] [Full Text: https://doi.org/10.1007/BF00284430]
Huh, T.-L., Kim, Y.-O., Oh, I.-U., Song, B. J., Inazawa, J. Assignment of the human mitochondrial NAD(+)-specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1-q25.2 by in situ hybridization. Genomics 32: 295-296, 1996. Note: Erratum: Genomics 35: 274 only, 1996. [PubMed: 8833160] [Full Text: https://doi.org/10.1006/geno.1996.0120]
Kim, Y.-O., Oh, I.-U., Park, H.-S., Jeng, J., Song, B. J., Huh, T.-L. Characterization of a cDNA clone for human NAD(+)-specific isocitrate dehydrogenase alpha-subunit and structural comparison with its isoenzymes from different species. Biochem. J. 308: 63-68, 1995. [PubMed: 7755589] [Full Text: https://doi.org/10.1042/bj3080063]
Peter, V. G., Nikopoulos, K., Quinodoz, M., Granse, L., Farinelli, P., Superti-Furga, A., Andreasson, S., Rivolta, C. A novel missense variant in IDH3A causes autosomal recessive retinitis pigmentosa. Ophthalmic Genet. 40: 177-181, 2019. [PubMed: 31012789] [Full Text: https://doi.org/10.1080/13816810.2019.1605391]
Pierrache, L. H. M., Kimchi, A., Ratnapriya, R., Roberts, L., Astuti, G. D. N., Obolensky, A., Beryozkin, A., Tjon-Fo-Sang, M. J. H., Schuil, J., Klaver, C. C. W., Bongers, E. M. H. F., Haer-Wigman, L., and 9 others. Whole-exome sequencing identifies biallelic IDH3A variants as a cause of retinitis pigmentosa accompanied by pseudocoloboma. Ophthalmology 124: 992-1003, 2017. [PubMed: 28412069] [Full Text: https://doi.org/10.1016/j.ophtha.2017.03.010]
Sun, W., Zhang, Q. A novel variant in IDH3A identified in a case with Leber congenital amaurosis accompanied by macular pseudocoloboma. Ophthalmic Genet. 39: 662-663, 2018. [PubMed: 30058936] [Full Text: https://doi.org/10.1080/13816810.2018.1502788]