title: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.
abstract: 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 Arg(140) 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.
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Kranendijk
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Emile
authors.initials: E
authors.lastname: van Schaftingen
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: Warsha A
authors.initials: WA
authors.lastname: Kanhai
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Neil R
authors.initials: NR
authors.lastname: Buist
authors.forename: Anibh M
authors.initials: AM
authors.lastname: Das
authors.forename: Johannis B
authors.initials: JB
authors.lastname: de Klerk
authors.forename: Annette S
authors.initials: AS
authors.lastname: Feigenbaum
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: Floris C
authors.initials: FC
authors.lastname: Hofstede
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Holme
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Rám N
authors.initials: RN
authors.lastname: Sukhai
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: D000293:Adolescent; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D005977:Glutarates / Q000378:metabolism* / Q000652:urine; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human