IDH2 Mutations in Patients with D-2-Hydroxyglutaric Aciduria

• Published in: Science (American Association for the Advancement of Science) Vol. 330; no. 6002; p. 336
• Main Authors: Kranendijk, Martijn, Struys, Eduard A, van Schaftingen, Emile, Gibson, K. Michael, Kanhai, Warsha A, van der Knaap, Marjo S, Amiel, Jeanne, Buist, Neil R, Das, Anibh M, de Klerk, Johannis B, Feigenbaum, Annette S, Grange, Dorothy K, Hofstede, Floris C, Holme, Elisabeth, Kirk, Edwin P, Korman, Stanley H, Morava, Eva, Morris, Andrew, Smeitink, Jan, Sukhai, Rám N, Vallance, Hilary, Jakobs, Cornelis, Salomons, Gajja S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 15.10.2010; The American Association for the Advancement of Science
• Subjects: Adolescent; Aminoacid disorders; Annan klinisk medicin; Biological and medical sciences; Brain Diseases, Metabolic, Inborn - genetics; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; BREVIA; Cancer; Child; Child, Preschool; Disorders; Enzymes; Errors of metabolism; Female; Genes; Genetic mutation; Genomics; Germ-Line Mutation; Glioma; Glutarates - metabolism; Glutarates - urine; Heterozygote; Human; Humans; Infant; Isocitrate Dehydrogenase - chemistry; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Isocitrates; Male; Materials; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Medical sciences; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Metabolic diseases; Metabolic disorders; Mosaicism; Mutation; Mutations; Neoplasms - genetics; Neoplasms - metabolism; Other Clinical Medicine; Patients; Residues; Young Adult; Human; Enzyme; Pathogenesis; Isocitrate dehydrogenase (NADP; Aciduria; Metabolic diseases; ); Genetic disease; Gene; Aminoacid; Genetics; Oxidoreductases; Mutation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1192632

Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to D-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue Arg¹⁴⁰ in 15 unrelated patients with D-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer.