title: A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria.
abstract: The purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. It is concluded that L-2-hydroxyglutarate is normally metabolized to alpha-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect of L-2-hydroxyglutarate on the central nervous system.
authors.affiliation: Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Avenue Hippocrate 75, B-1200 Brussels, Belgium.
authors.forename: Rim
authors.initials: R
authors.lastname: Rzem
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.forename: Gaëtane
authors.initials: G
authors.lastname: Noël
authors.forename: Sophie
authors.initials: S
authors.lastname: Goffette
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nassogne
authors.forename: Brahim
authors.initials: B
authors.lastname: Tabarki
authors.forename: Christina
authors.initials: C
authors.lastname: Schöller
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D005977:Glutarates / Q000652:urine*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D005977:Glutarates; D005182:Flavin-Adenine Dinucleotide; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase