TY - JOUR
T1 - Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma
AU - van Lith, Sanne A. M.
AU - Navis, Anna C.
AU - Lenting, Krissie
AU - Verrijp, Kiek
AU - Schepens, Jan T. G.
AU - Hendriks, Wiljan J. A. J.
AU - Schubert, Nil A.
AU - Venselaar, Hanka
AU - Wevers, Ron A.
AU - van Rooij, Arno
AU - Wesseling, Pieter
AU - Molenaar, Remco J.
AU - van Noorden, Cornelis J. F.
AU - Pusch, Stefan
AU - Tops, Bastiaan
AU - Leenders, William P. J.
PY - 2016/7/27
Y1 - 2016/7/27
N2 - 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 (alpha-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce alpha-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of alpha-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 alpha-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-alpha-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 alpha-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
AB - 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 (alpha-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce alpha-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of alpha-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 alpha-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-alpha-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 alpha-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
U2 - https://doi.org/10.1038/srep30486
DO - https://doi.org/10.1038/srep30486
M3 - Article
C2 - 27460417
SN - 2045-2322
VL - 6
SP - 30486
JO - Scientific reports
JF - Scientific reports
ER -