IDH2 mutations in patients with D-2-hydroxyglutaric aciduria

  • Science. 2010 Oct 15;330(6002):336. doi: 10.1126/science.1192632.
Martijn Kranendijk  1 ,  Eduard A Struys ,  Emile van Schaftingen ,  K Michael Gibson ,  Warsha A Kanhai ,  Marjo S van der Knaap ,  Jeanne Amiel ,  Neil R Buist ,  Anibh M Das ,  Johannis B de Klerk ,  Annette S Feigenbaum ,  Dorothy K Grange ,  Floris C Hofstede ,  Elisabeth Holme ,  Edwin P Kirk ,  Stanley H Korman ,  Eva Morava ,  Andrew Morris ,  Jan Smeitink ,  Rám N Sukhai ,  Hilary Vallance ,  Cornelis Jakobs ,  Gajja S Salomons
Affiliations
  • 1. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, Netherlands.
PMID: 20847235 DOI: 10.1126/science.1192632
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.