Alternative titles; symbols
HGNC Approved Gene Symbol: IDH2
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38): 15:90,083,045-90,102,468 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | D-2-hydroxyglutaric aciduria 2 | 613657 | 3 |
IDH2 is a mitochondrial NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) that catalyzes oxidative decarboxylation of isocitrate to alpha-ketoglutarate, producing NADPH. By providing NADPH for NADPH-dependent antioxidant enzymes, IDH2 plays a major role in controlling the mitochondrial redox balance and mitigating cellular oxidative damage (Park et al., 2008).
Using a subtraction approach to identify genes upregulated in activated B cells, followed by screening a heart cDNA library, Luo et al. (1996) cloned IDH2, which they called mNADP-IDH. The deduced 419-amino acid protein contains 7 conserved cysteines, including 1 located in the putative NADP-binding pocket, 7 residues implicated in binding of isocitrate and Mg(2+), and 2 conserved N-glycosylation sites. Northern blot analysis detected very high expression in heart and skeletal muscle, with little to no expression in other tissues examined.
Huh et al. (1996) quoted preliminary observations by fluorescence in situ hybridization indicating that the IDH2 gene maps to chromosome 15q26.1; see the report by Oh et al. (1996).
Luo et al. (1996) showed that basal IDH2 activity in mitochondria prepared from several human tissues correlated with IDH2 mRNA levels in these tissues. IDH2 mRNA expression and enzymatic activity were low in resting human tonsillar T and B lymphocytes, but they were induced following mitogen stimulation. Induction of IDH2 was detected in late G1 phase after activation, but it was independent of the cell cycle. Cytosolic IDH1 (147700) activity was unaffected by lymphocyte activation. The immunosuppressants rapamycin and cyclosporin A inhibited mitogen-induced expression of IDH2 in T and B cells.
Myeloperoxidase (MPO; 606989) catalyzes formation of hypochlorous acid (HOCl), which plays a major role in the immune system by killing bacteria and other invading pathogens. However, excessive generation of HOCl can cause tissue damage. Park et al. (2008) showed that HOCl caused a concentration-dependent loss of mouse Idpm activity in vitro. Idpm activity was protected from HOCl-induced damage by cotreatment with thiols or by addition of the substrates NADP+ and isocitrate. Treatment of HeLa cells with small interfering RNA directed against IDPM exacerbated HOCl-induced generation of reactive oxygen species, cellular oxidative damage, and mitochondrial dysfunction. Park et al. (2008) concluded that HOCl causes cellular oxidative damage by oxidizing critical cysteine residues in the IDPM active site, leading to IDPM inactivation and perturbation of the cellular antioxidant defense system.
Lu et al. (2012) reported that 2-hydroxyglutarate (2HG)-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumor samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in nontransformed cells, Lu et al. (2012) tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, Lu et al. (2012) found that the 2HG-inhibitable H3K9 demethylase KDM4C (605469) was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Lu et al. (2012) concluded that, taken together, their data demonstrated that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of nontransformed cells.
Koivunen et al. (2012) showed that the R-enantiomer of 2HG (R-2HG), produced by cancer-associated mutant IDH1 or IDH2, but not S-2HG, stimulates EGLN (e.g., EGLN1; 606425) activity, leading to diminished HIF (see 603348) levels, which enhances the proliferation and soft agar growth of human astrocytes. Koivunen et al. (2012) concluded that their findings defined an enantiomer-specific mechanism by which the R-2HG that accumulates in IDH mutant brain tumors promotes transformation.
Saha et al. (2014) showed that mutant IDH1 and IDH2 block liver progenitor cells from undergoing hepatocyte differentiation through the production of 2-hydroxyglutarate (2HG) and suppression of HNF4A (600281), a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant Idh in adult liver showed an aberrant response to hepatic injury, characterized by Hnf4a silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and KRAS (190070) mutations, genetic alterations that coexist in a subset of human intrahepatic cholangiocarcinomas (IHCCs), cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. Saha et al. (2014) concluded that their studies provided a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and presented a novel genetically engineered mouse model of IDH-driven malignancy.
Flavahan et al. (2016) showed that human IDH1 and IDH2 mutant gliomas exhibit hypermethylation at cohesin- (see 606462) and CTCF (604167)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topologic domains and aberrant gene activation. Flavahan et al. (2016) specifically demonstrated that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA (173490), a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restored insulator function and downregulated PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motifs in IDH wildtype gliomaspheres upregulated PDGFRA and increased proliferation.
Yoshimi et al. (2019) used analysis of transcriptomes from 982 patients with acute myeloid leukemia (AML; 601626) to identify frequent overlap of mutations in IDH2 and SRSF2 (600813) that together promote leukemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, coexpression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, coexpression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3 (611347), a member of the integrator complex, concordant with increased stalling of RNA polymerase II. Aberrant INTS3 splicing contributed to leukemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. Yoshimi et al. (2019) concluded that their data identified a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukemias, provided functional evidence that mutations in splicing factors drive myeloid malignancy development, and identified spliceosomal changes as a mediator of IDH2-mutant leukemogenesis.
D-2-Hydroxyglutaric Aciduria 2
In 15 of 17 cases of D-2-hydroxyglutaric aciduria (see D2HGA2, 613657) without mutation in the D2HGDH gene (609186), Kranendijk et al. (2010) identified a heterozygous mutation in the IDH2 gene. Fourteen of the 15 patients had an arg140-to-gln mutation (R140Q; 147650.0001) and 1 had an arg140-to-gly mutation (R140G; 147650.0002). In 8 of 9 sets of parents this mutation could not be detected, indicating a de novo mutation and that D2HGA2 is an autosomal dominant trait. The mother of 1 patient demonstrated germline mosaicism.
Somatic Mutations
Yan et al. (2009) determined the sequence of the IDH1 (147700) gene and related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Yan et al. (2009) identified mutations that affected amino acid 132 of IDH1 in more than 70% of World Health Organization (WHO) grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wildtype IDH genes. Each of the 4 tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. Yan et al. (2009) concluded that mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
For a discussion of somatic IDH1 and IDH2 mutations in multiple enchondromatosis, see Ollier disease (166000) and Maffucci syndrome (614569).
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the IDH1 or IDH2 genes in 39/200 (20%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that genes mutated almost exclusively in founding clones in their study included IDH2 (13 of 14 mutations in founding clones). They identified several other genes that contained mutations they considered probable initiators, and other genes mutations in which were considered probably cooperating mutations.
Mutations at arginines 140 and 172 in IDH2 are known to cause the neomorphic ability of the protein to convert alpha-ketoglutarate to 2-hydroxyglutaric acid (2HG). Akbay et al. (2014) created knockin transgenic mouse strains with R140Q and R172K mutations. Embryonic activation of these mutations resulted in severe phenotypes including partial embryonic lethality, runting, tremors, seizures, hydrocephalus, and cardiac hypertrophy, with death between 3 and 7 weeks. Conditional adult activation of the mutations in the lung, spleen, kidney, brain, and heart resulted in lethargy, shortness of breath, enlarged hearts, cardiomyopathy with heart scarring and cardiomyocyte apoptosis, and circulatory congestion associated with cardiac failure. These symptoms developed faster in the R172K mice than the R140Q mice. The cardiac and skeletal muscles showed defective sarcomere organization and mitochondria, and levels of TCA cycle intermediates were also decreased in the heart. In the brain, the IDH2 mutations caused diffuse vacuolar leukoencephalopathy in the white and gray matter along with membranous debris-filled vacuoles in the neuronal axons, but did not affect apoptosis. Histone analysis in heart tissue showed increased levels of H3K4me3 but no changes in H3K27me3 or H3K36me3. Gene expression profiling showed upregulation of glycogen biosynthesis, downregulation of glycogen degradation, and upregulation of collagen biosynthesis and reorganization. Chemical staining showed an increase in glycogen accumulation in the muscle, but no changes in lipid accumulation. Restoring wildtype IDH2 expression rescued the mouse phenotype, as measured by decreased levels of serum 2HG, increased heart function, and increased overall survival. Nude mice with xenografted IDH2 R140Q-expressing U87 cells had larger hearts and increased apoptotic myocytes compared to mice with control tumors, suggesting that the 2HG produced by cells with mutant IDH2 acts in a paracrine fashion to affect heart function.
In 14 of 15 patients with D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657), Kranendijk et al. (2010) identified a G-to-A transition at nucleotide 419 of the IDH2 gene, resulting in an arg-to-gln substitution at codon 140 (R140Q). This mutation occurred de novo in 13 of the 14 patients but was identified in 1 patient's mother with somatic and germline mosaicism. Somatic R140Q mutation had been identified in acute myeloid leukemia and shown to lead to abnormal production of D-2-hydroxyglutaric acid (Ward et al., 2010).
Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the 419G-A (R140Q) mutation in IDH2 had occurred de novo.
Inhibition of Mutation in Cancer
Wang et al. (2013) developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. Wang et al. (2013) concluded that these data provided proof of concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
In 1 patient with D-2-hydroxyglutaric aciduria (D2HGA2; 613657), Kranendijk et al. (2010) identified a C-to-G transversion at nucleotide 418 of the IDH2 gene, resulting in an arg-to-gly substitution at codon 140 (R140G). This mutation arose de novo in the affected individual.
In a patient with D2HGA2, Nota et al. (2013) identified heterozygosity for the R140Q mutation. The mutation was inherited from her unaffected mother, who was a mosaic carrier.
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Yoshimi, A., Lin, K.-T., Wiseman, D. H., Rahman, M. A., Pastore, A., Wang, B., Lee, S. C.-W., Micol, J.-B., Zhang, X. J., de Botton, S., Penard-Lacronique, V., Stein, E. M., and 17 others. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 574: 273-277, 2019. [PubMed: 31578525] [Full Text: https://doi.org/10.1038/s41586-019-1618-0]