title: Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma.
abstract: The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite.
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Sanne A M
authors.initials: SA
authors.lastname: van Lith
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Krissie
authors.initials: K
authors.lastname: Lenting
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.affiliation: Department of Cell Biology, Radboud Institute for Molecular Life Sciences, The Netherlands.
authors.forename: Jan T G
authors.initials: JT
authors.lastname: Schepens
authors.affiliation: Department of Cell Biology, Radboud Institute for Molecular Life Sciences, The Netherlands.
authors.forename: Wiljan J A J
authors.initials: WJ
authors.lastname: Hendriks
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Nil A
authors.initials: NA
authors.lastname: Schubert
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, The Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Translational Metabolic Laboratory, Department Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Translational Metabolic Laboratory, Department Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Arno
authors.initials: A
authors.lastname: van Rooij
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.|Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Tops
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D005977:Glutarates / Q000378:metabolism; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007523:Isocitrates / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009249:NADP / Q000378:metabolism; D060787:Neoplasm Grading; D055503:Protein Multimerization
chemical_list: D005977:Glutarates; D007523:Isocitrates; C019417:alpha-hydroxyglutarate; D009249:NADP; C034219:isocitric acid; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human