Alternative titles; symbols
HGNC Approved Gene Symbol: IDH1
Cytogenetic location: 2q34 Genomic coordinates (GRCh38) : 2:208,236,227-208,255,071 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q34 | {Glioma, susceptibility to, somatic} | 137800 | 3 |
IDH1 is a dimeric cytosolic NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate (Nekrutenko et al., 1998).
By RT-PCR of placenta RNA, followed by PCR of an adult liver cDNA library, Nekrutenko et al. (1998) cloned human IDH1. The deduced 414-amino acid protein has a calculated molecular mass of 46.7 kD. It contains a dehydrogenase and isopropylmalate dehydrogenase signature sequence, 7 conserved residues predicted to be involved in isocitrate binding, and a C-terminal peroxisomal-targeting signal. Human IDH1 shares about 95% amino acid identity with Idh1 from mouse and 2 species of vole.
By searching databases for sequences similar to S. cerevisiae Idp3, Geisbrecht and Gould (1999) identified a human colon carcinoma cDNA encoding IDH1, which they called PICD. The deduced protein shares 59% identity with yeast Idp3. Western blot analysis of a human hepatocellular carcinoma cell line detected PICD at an apparent molecular mass of 46 kD. In fractionated cells, most PICD associated with the cytosolic fraction, although a significant amount colocalized with a peroxisomal marker. In rat liver cells, about 27% of total Picd protein was associated with peroxisomes.
Geisbrecht and Gould (1999) found that purified recombinant human PICD catalyzed oxidative decarboxylation of isocitric acid and required NADP+ for the reaction. In addition, human PICD could complement the oleate growth defect in Idp3-null yeast.
Shechter et al. (2003) found that expression of IDH1 mRNA increased 2.3-fold and IDH1 activity increased 63% in sterol-deprived HepG2 cells. The IDH1 promoter region was activated by expression of SREBP1A (SREBF1; 184756) and, to a lesser degree, SREBP2 (SREBF2; 600481). Electrophoretic mobility shift assays confirmed preferential binding of SREBP1A to an SREBP-binding element located at nucleotides -44 to -25 in the IDH1 promoter region. Shechter et al. (2003) concluded that IDH1 activity is coordinately regulated with the cholesterol and fatty acid biosynthetic pathways, suggesting that IDH1 provides the cytosolic NADPH required by these pathways.
Using 2-dimensional PAGE and Western blot analysis, Memon et al. (2005) found that expression of IDPC was downregulated in a poorly differentiated bladder cancer cell line compared with a well-differentiated bladder cancer cell line. Tissue biopsies of late-stage bladder cancers also showed IDPC downregulation compared with early-stage bladder cancers.
Ronnebaum et al. (2006) found that downregulation of Icdc via small interfering RNA impaired glucose-stimulated insulin secretion in 2 rat insulinoma cell lines and in primary rat islets. Suppression of Icdc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, as well as total cellular NADP(H) content. Metabolic profiling of 8 organic acids in cell extracts revealed that suppression of Icdc increased lactate production, consistent with attenuation of pyruvate cycling, with no significant changes in other intermediates. Ronnebaum et al. (2006) concluded that ICDC plays an important role in the control of glucose-stimulated insulin secretion.
Metallo et al. (2012) showed that human cells use reductive metabolism of alpha-ketoglutarate to synthesize acetyl-coenzyme A (AcCoA) for lipid synthesis. This IDH1-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived alpha-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumor suppressor protein (VHL; 608537) preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. Metallo et al. (2012) concluded that their results identified a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.
Mullen et al. (2012) showed that tumor cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent IDH1, and subsequent metabolism of glutamine-derived citrate provides both the AcCoA for lipid synthesis and the 4-carbon intermediates needed to produce the remaining citric acid cycle (CAC) metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the electron transport chain (ECT), in patient-derived renal carcinoma cells with mutations in fumarate hydratase (136850), and in cells with normal mitochondria subjected to acute pharmacologic ECT inhibition. Mullen et al. (2012) concluded that their findings revealed the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumor cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.
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.
Turcan et al. (2012) showed that mutation of IDH1 establishes the glioma CpG island methylator (G-CIMP) phenotype by remodeling the methylome. This remodeling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrated a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes altered specific histone marks, induced extensive DNA hypermethylation, and reshaped the methylome in a fashion that mirrored the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activated key gene expression programs, characterized G-CIMP-positive proneural glioblastomas but not other glioblastomas, and were predictive of improved survival. Turcan et al. (2012) concluded that their findings demonstrated that IDH mutation is the molecular basis of CIMP in gliomas, provided a framework for understanding oncogenesis in these gliomas, and highlighted the interplay between genomic and epigenomic changes in human cancers.
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 (147650) 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.
Xu et al. (2004) performed structural studies of human IDH1 in complex with NADP and with NADP, isocitrate, and Ca(2+) and identified 3 conformational states of the enzyme. A structural segment at the active site assumed a loop conformation in the open, inactive state, a partially unraveled alpha helix in the semi-open, intermediate state, and an alpha helix in the closed, active state. In the active conformation, asp279 formed a hydrogen bond with Ca(2+) to participate in the catalytic reaction. In the inactive conformation, asp279 formed a hydrogen bond with ser94 and hindered access of isocitrate to the active site. Since serine phosphorylation inactivates E. coli Idh, Xu et al. (2004) proposed that the hydrogen bond formed between asp279 and ser94 may mimic an inactivating serine phosphorylation.
Shechter et al. (2003) determined that the IDH1 gene contains 10 exons and spans 18.9 kb. The first 2 exons are untranslated and contain 5 putative transcription start sites. Nucleotides -44 to -25 contain an SREBP-binding element (GTGGGCTGAG).
Chen et al. (1972) found rare variants of soluble IDH and concluded that the structural gene is probably autosomal and that it is distinct from the locus governing the mitochondrial form. Shows (1972) presented cell hybridization data suggesting that soluble malate dehydrogenase (MDH1; 154200) and IDH are syntenic. Using the cell-hybrid method which relies on interspecies variation rather than polymorphism, Boone et al. (1972) concluded that the IDH locus is on chromosome 20. The assignment of soluble IDH and soluble MDH to chromosome 20 was withdrawn (Ruddle, 1973). Creagan et al. (1974) presented evidence that these 2 syntenic loci are on chromosome 2. From study of a balanced reciprocal translocation (X;2)(p22;q32) in man-mouse hybrids, Van Cong (1976) concluded that IDH1 is located in the region 2q32-qter. By dosage effect in cases of chromosome 2 aberrations, Narahara et al. (1985) concluded that the IDH1 locus is on chromosome 2q33.3, probably in the proximal portion.
Role in Gliomas
To identify the genetic alterations in glioblastoma multiforme (GBM; see 137800), Parsons et al. (2008) sequenced 20,661 protein-coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, Parsons et al. (2008) found recurrent mutations in the active site of IDH1 in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. Parsons et al. (2008) concluded that their studies demonstrated the value of unbiased genomic analyses in the characterization of human brain cancer and identified a potentially useful genetic alteration for the classification and targeted therapy of GBMs. Parsons et al. (2008) found that the hazard ratio for death among 79 patients with wildtype IDH1, as compared to 11 with mutant IDH1, was 3.7 (95% confidence interval, 2.1 to 6.5; p less than 0.001). The median survival was 3.8 years for patients with mutated IDH1, as compared to 1.1 years for patients with wildtype IDH1. Parsons et al. (2008) found that a majority of tumors analyzed had alterations in genes encoding components of each of the TP53 (191170), RB1 (614041), and PI3K (see 171834) pathways. Parsons et al. (2008) detected somatic mutation in IDH1 at arginine-132 (R132) in 12 of 105 GBMs. In 10 of these tumors the mutation was R132H (147700.0001), and in the other 2 it was R132S. In a further screening for IDH1 mutations, 6 of 44 GBMs carried somatic mutations affecting R132. In total, 18 of 149 GBMs (12%) analyzed had alterations in IDH1.
Yan et al. (2009) determined the sequence of the IDH1 gene and related IDH2 (147650) 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.
Zhao et al. (2009) showed that mutation at arginine-132 (R132) of IDH1 (see 147700.0001) impairs the enzyme's affinity for its substrate and dominantly inhibits wildtype IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduced formation of the enzyme product, alpha ketoglutarate (alpha-KG), and increased the levels of hypoxia-inducible factor subunit HIF1-alpha (603348), a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF1-alpha levels was reversible by an alpha-KG derivative. HIF1-alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, Zhao et al. (2009) concluded that IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF1 pathway.
Dang et al. (2009) showed that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of alpha-ketoglutarate to D-2-hydroxyglutarate (2HG). Structural studies demonstrated that when arg132 is mutated to his (R132H), residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism (Aghili et al., 2009) (see 600721). Similarly, in human malignant gliomas harboring IDH1 mutations, Dang et al. (2009) found markedly elevated levels of 2HG. Dang et al. (2009) concluded that their data demonstrated that the IDH1 mutations result in production of the oncometabolite 2HG, and indicated that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
In a retrospective study of 49 progressive astrocytomas, 42 (86%) of which had somatic mutations in the IDH1 gene, Dubbink et al. (2009) found that the presence of IDH1 mutations was significantly associated with increased patient survival (median survival, 48 vs 98 months), but did not affect outcome of treatment with temozolomide.
Rohle et al. (2013) examined the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 (see 602810) and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant, but not IDH1-wildtype, glioma cells without appreciable changes in genomewide DNA methylation. Rohle et al. (2013) concluded that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.
Yanchus et al. (2022) identified the rs55705857-G allele (613040.0001) as the causative risk variant for susceptibility to IDH-mutant low-grade glioma (LGG) at the 8q24.21 locus (GLM7; 613032).
Role in Acute Myeloid Leukemia
Mardis et al. (2009) identified the R132C mutation in 8 of 188 acute myeloid leukemia (AML; 601626) samples and the R132H mutation in 7 of 188 samples. The R132S mutation was seen in 1 sample. Mutation of the IDH1 gene was strongly correlated with a normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%).
Schnittger et al. (2010) identified somatic heterozygous mutations in the IDH1 gene in samples from 93 (6.6%) of 1,414 patients with AML. Five different mutations at codon arg132 were observed, with R132C being the most common (54.8%). Patients with IDH1 mutations more commonly had an immature immunophenotype (p less than 0.001), were female (p = 0.003), had shorter overall survival (p = 0.110), a shorter event-free survival (p less than 0.003), and a higher cumulative risk for relapse (p = 0.001). More than 73% of all IDH1-mutated cases had additional molecular defects, most frequently in NPM1 (164040), compatible with a multiple-hit hypothesis of AML pathogenesis. The data indicated that IDH1 status may add information regarding characterization and prognostication in AML.
Losman et al. (2013) found that expression of the canonical IDH1 mutant R132H in human erythroleukemia cells and immortalized granulocyte-macrophage progenitor cells promoted growth factor independence and impaired differentiation, 2 hallmarks of leukemic transformation. These effects could be recapitulated by (R)-2-hydroxyglutarate, but not (S)-2-hydroxyglutarate, despite the fact that (S)-2-hydroxyglutarate more potently inhibits enzymes, such as the 5-prime-methylcytosine TET2 (300255), that had been linked to the pathogenesis of IDH mutant tumors. Losman et al. (2013) provided evidence that this paradox relates to the ability of (S)-2-hydroxyglutarate but not not (R)-2-hydroxyglutarate to inhibit the EglN (606425) prolyl hydroxylases. Additionally, Losman et al. (2013) showed that transformation by (R)-2-hydroxyglutarate is reversible.
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 (147650) 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 IDH1 was among several genes in their study whose mutations were often found in subclones, suggesting that they are often cooperating mutations. The authors also identified other genes that contained mutations they considered probable initiators.
Role in Multiple Enchondromatosis
For a discussion of somatic IDH1 and IDH2 mutations in multiple enchondromatosis, see Ollier disease (166000) and Maffucci syndrome (614569).
Sasaki et al. (2012) reported the characterization of conditional knockin mice in which the most common IDH1 mutation, R132H, is inserted into the endogenous murine Idh1 locus and is expressed in all hematopoietic cells or specifically in cells of the myeloid lineage. These mutants showed increased numbers of early hematopoietic progenitors and developed splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, the myeloid-specific knockin cells had hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. Sasaki et al. (2012) concluded that, to their knowledge, theirs was the first study to describe the generation and characterization of conditional IDH1(R132H)-knockin mice, and also the first to report the induction of a leukemic DNA methylation signature in a mouse model.
Yanchus et al. (2022) created an Idh1(R132H) (147700.0001)-driven mouse model of low-grade glioma (LGG) and found that disruption of the orthologous rs55705857 LGG risk locus (613040.0001) accelerated tumor development from 472 to 172 days and increased penetrance from 30% to 75%.
In 5 of 22 glioblastoma multiforme (GBM) tumors (see 137800), Parsons et al. (2008) detected a change of guanine to adenine at position 395 of the IDH1 transcript (G395A), leading to the replacement of arginine with histidine at amino acid residue 132 of the protein (arg132 to his, R132H). Five further GBMs were found to carry the mutation in a subsequent screen. The R132 residue is evolutionarily conserved and is localized to the substrate-binding site, where it forms hydrophilic interactions with the alpha-carboxylate of isocitrate.
Bralten et al. (2011) found that overexpression of IDH1-R132H in established glioma cell lines resulted in decreased proliferation and more contact-dependent cell migration compared to wildtype. Intracerebral injection of IDH1-R132H in mice, as compared to injection of wildtype, resulted in increased survival and even absence of tumor in 1 mouse. Reduced cellular proliferation was associated with accumulation of D-2-hydroxyglutarate that is produced by the R132H variant protein. The decreased proliferation was not associated with increased apoptosis, but was associated with decreased AKT1 (164730) activity. The findings indicated that R132H dominantly reduces aggressiveness of established glioma cell lines in vitro and in vivo. Bralten et al. (2011) noted that the findings were apparently contradictory because the presence of an IDH1 mutation was thought to contribute to tumorigenesis; the authors suggested that IDH1 mutations may be involved in tumor initiation and not in tumor progression. IDH1-mutant tumors are typically low-grade and often slow-growing.
Schumacher et al. (2014) demonstrated that the R132H variant in the IDH1 gene contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on MHC class II and induce mutation-specific CD4+ T-helper-1 responses. CD4+ T-helper-1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognized IDH1(R132H). Peptide vaccination of humanized mice with IDH1(R132H) p123-142 resulted in an effective MHC class II-restricted mutation-specific antitumor immune response and control of preestablished syngeneic IDH1(R132H)-expressing tumors in a CD4+ T-cell-dependent manner.
Yanchus et al. (2022) identified the rs55705857-G allele (613040.0001) as the causative risk variant for susceptibility to IDH-mutant low-grade glioma (LGG) at the 8q24.21 locus (GLM7; 613032).
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