IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.
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.
Kranendijk
Martijn
M
Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, Netherlands.
Struys
Eduard A
EA
van Schaftingen
Emile
E
Gibson
K Michael
KM
Kanhai
Warsha A
WA
van der Knaap
Marjo S
MS
Amiel
Jeanne
J
Buist
Neil R
NR
Das
Anibh M
AM
de Klerk
Johannis B
JB
Feigenbaum
Annette S
AS
Grange
Dorothy K
DK
Hofstede
Floris C
FC
Holme
Elisabeth
E
Kirk
Edwin P
EP
Korman
Stanley H
SH
Morava
Eva
E
Morris
Andrew
A
Smeitink
Jan
J
Sukhai
Rám N
RN
Vallance
Hilary
H
Jakobs
Cornelis
C
Salomons
Gajja S
GS
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
D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human