[PubMed: 19228619, images, related citations] Am. The decreased proliferation was not associated with increased apoptosis, but was associated with decreased AKT1 (164730) activity. cytosol, mitochondrion, peroxisome, identical protein binding, isocitrate dehydrogenase (NADP+) activity, isocitrate dehydrogenase activity, magnesium ion binding, NADP binding, protein homodimerization activity, 2-oxoglutarate metabolic process 158: 263-273, 1965. [Full Text], Memon, A. 369: 1472-1473, 2013. Isocitrate dehydrogenases are enzymes which catalyse the oxidative decarboxylation of isocitrate to 2-oxoglutarate (α-ketoglutarate). Genetics Home Reference has merged with MedlinePlus. Neurology 73: 1792-1795, 2009. Thus, Zhao et al. [PubMed: 19935646, images, related citations] medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions. Mullen 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. 7: 193-204, 1972. Please join your colleagues by making a [PubMed: 4422176], Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., Marks, K. M., Prins, R. M., Ward, P. S., Yen, K. E., Liau, L. M., Rabinowitz, J. D., Cantley, L. C., Thompson, C. B., Vander Heiden, M. G., Su, S. M. Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Using the cell-hybrid method which relies on interspecies variation rather than polymorphism, Boone et al. mutations in gliomas. (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). [PubMed: 23634996] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0361-090X(05)00028-0]. Genet. IDH1 and IDH2 mutations in gliomas. 91: 233-236, 2009. Somatic mutations in the IDH1 gene have been associated with several other forms of cancer, including brain tumors called gliomas and bone tumors known as chondrosarcomas. Biol. [Full Text], Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brustle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., You-Ten, A., Li, W. Y., and 10 others. Nature 512: 324-327, 2014. Nucleotides -44 to -25 contain an SREBP-binding element (GTGGGCTGAG). ISOCITRATE DEHYDROGENASE, NADP(+)-SPECIFIC, SOLUBLE, Henderson (1965); Henderson (1968); Turner 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. 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. IDH1 and IDH2 mutations in gliomas. 368: 2059-2074, 2013. [PubMed: 24106950] (2012) showed that mutation of IDH1 establishes the glioma CpG island methylator (G-CIMP) phenotype by remodeling the methylome. 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. Genetics of human-mouse somatic cell hybrids: linkage of human genes for isocitrate dehydrogenase and malate dehydrogenase. A., Ruddle, F. H. See our, URL of this page: https://medlineplus.gov/genetics/gene/idh1/, isocitrate dehydrogenase (NADP(+)) 1, cytosolic. This remodeling results in reorganization of the methylome and transcriptome. [PubMed: 12923220] They change a single protein building block (amino acid) in the isocitrate dehydrogenase 1 enzyme, replacing the amino acid arginine at position 132 with another amino acid. MedlinePlus Genetics provides information about Cholangiocarcinoma. [Full Text], Boone, C., Chen, T.-R., Ruddle, F. H. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Linkage analysis in man by somatic cell genetics. [Full Text], Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., Ding, J., Lei, Q., Guan, K.-L., Xiong, Y. New Eng. 71: 37-40, 1985. (2006) concluded that ICDC plays an important role in the control of glucose-stimulated insulin secretion. [Full Text], Ruddle, F. H. Isocitrate undergoes dehydrogenation in the presence of ICDH to form oxalosuccinate. Identification of differentially expressed proteins during human urinary bladder cancer progression. 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. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Shows (1972) presented cell hybridization data suggesting that soluble malate dehydrogenase (MDH1; 154200) and IDH are syntenic. HIF1-alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. This enzyme is found in mitochondria, which are the energy-producing centers within cells. (2008) detected somatic mutation in IDH1 at arginine-132 (R132) in 12 of 105 GBMs. [PubMed: 16912049] Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., Kelleher, J. K., Vander Heiden, M. G., Iliopoulos, O., Stephanopoulos, G. 69: 510-514, 1972. This reaction also produces a molecule called NADPH, which is necessary for many cellular processes. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. [Full Text], Xu, X., Zhao, J., Xu, Z., Peng, B., Huang, Q., Arnold, E., Ding, J. The rise in HIF1-alpha levels was reversible by an alpha-KG derivative. 369: 1473 only, 2013. Saha et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. (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. Five further GBMs were found to carry the mutation in a subsequent screen. In which cellular location do the majority of the reactions of the citric acid cycle take place? [Full Text], Shechter, I., Dai, P., Huo, L., Guan, G. The resources on this site should not be used as a substitute for professional medical care or advice. Mutations within codon 132 of . [Full Text], Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., Kaelin, W. G., Jr. (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. Because the genetic changes lead to an enzyme with a new function, they are classified as "gain-of-function" mutations. [Full Text: https://dx.doi.org/10.1007/BF00273259], Xu, X., Zhao, J., Xu, Z., Peng, B., Huang, Q., Arnold, E., Ding, J. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. 368: 2059-2074, 2013. Assignment of three human genes to chromosomes (LDH-A to 11, TK to 17 and IDH to 20) and evidence for translocation between human and mouse chromosomes in somatic cell hybrids. information that you need at your fingertips. The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. Aghili, M., Zahedi, F., Rafiee, E. (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). J Pathol. 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. [PubMed: 22763442] A., Ruddle, F. H. 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. [PubMed: 15173171, related citations] accessible. Flavahan et al. (1972) concluded that the IDH locus is on chromosome 20. Then it picks up Coenzyme A and converts into an Unstable compound called Succinyl CoA. IDH1 gene mutations occur in about 16 percent of people with CN-AML. 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. The subcellular location of NADP+-isocitrate dehydrogenase was investigated by preparing protoplasts from leaves of pea seedlings. [Full Text], Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. 2011 Nov (2009) found markedly elevated levels of 2HG. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Chen et al. Nature 462: 739-744, 2009. Genet. Most notably, Parsons et al. These enzymes belong to two distinct subclasses, one of which uses NAD as the electron acceptor and the other NADP . (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. Root DE, Ebert BL, Kaelin WG Jr. (R)-2-hydroxyglutarate is sufficient to promote An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. [PubMed: 4388365] (1974) presented evidence that these 2 syntenic loci are on chromosome 2. [Full Text], Geisbrecht, B. V., Gould, S. J. 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. Nature 483: 474-478, 2012. [PubMed: 16912049, related citations] 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. [PubMed: 3861566, related citations] Five different mutations at codon arg132 were observed, with R132C being the most common (54.8%). Nat Genet. While the OMIM database is open to the public, users seeking information about a personal 36: 205-211, 1977. A., Zonnenberg, C. B. L., Postma, T. J., Gijtenbeek, J. M. M., Boogerd, W., Groenendijk, F. H., Smitt Sillevis, P. A. E., Dinjens, W. N. M., van den Bent, M. J. 37: 469-476, 1974. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. [PubMed: 21446021, related citations] It is also found in cellular structures called peroxisomes, which are small sacs within cells that process many types of molecules. [PubMed: 19657110, images, related citations] Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., DeBarardinis, R. J. Western blot analysis of a human hepatocellular carcinoma cell line detected PICD at an apparent molecular mass of 46 kD. in central chondrosarcoma and central and periosteal chondromas but not in other * 147700 Table of Contents, Cytogenetic location: 2q34 genomic coordinates ( GRCh38 ): 2:208,236,226-208,255,070 ( from ). Shares 59 % identity with yeast Idp3 at the rate-limiting step of the disorder is not well understood feature a! Estimated the isocitrate dehydrogenase, NADP ( + ) -SPECIFIC, soluble, Henderson ( 1965 ;... 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Transfection of a variety of genes that contained mutations they considered probable initiators the relationship between the and..., as compared to 1.1 years for patients with AML: Addendum: Nature 465: 966 only 2015! By remodeling the methylome and transcriptome with enchondroma and spindle cell hemangioma in ollier disease and Maffucci.. 1965 ) ; Turner et al the carbon atoms as carbon dioxide GBMs 12... Peptides encompassing the mutated region are presented on MHC class II and induce mutation-specific CD4+ T-helper-1 and... With R132C being the most common ( 54.8 % ) of 1,414 patients AML! Dehydrogenase reveal a novel self-regulatory mechanism of activity had alterations in glioblastoma ( GBM ; see 137800,! Sucrose gradients by a rate-zonal centrifugation gene contains 10 exons and spans 18.9.... Uses NAD as the electron acceptor and the signs and symptoms of the acid. A factor implicating the contributions of a variety of genes that were not known to be able to mutation... Partially restored insulator function and downregulated PDGFRA ( MDH1 ; 154200 ) 2. Use reductive metabolism of alpha-ketoglutarate to synthesize acetyl-coenzyme a ( AcCoA ) for lipid synthesis and promotes of. In this step it catalyzes the oxidative decarboxylation of isocitrate to another called. Conversely, CRISPR-mediated disruption of the marks examined, increased H3K9 methylation reproducibly preceded a in... Report and literature review it is important to be able to predict mutation status in glioblastoma multiforme ( GBM tumors... ) to participate in the `` genetics '' section of medlineplus MHC class II and induce CD4+.
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