title: Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria.
abstract: d-2-hydroxyglutaric aciduria is a neurometabolic disorder with both a mild and a severe phenotype and with unknown etiology. Recently, a novel enzyme, d-2-hydroxyglutarate dehydrogenase, which converts d-2-hydroxyglutarate into 2-ketoglutarate, and its gene were identified. In the genes of two unrelated patients affected with d-2-hydroxyglutaric aciduria, we identified disease-causing mutations. One patient was homozygous for a missense mutation (c.1331T-->C; p.Val444Ala). The other patient was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele. Overexpression studies in HEK-293 cells of proteins containing the missense mutations showed a marked reduction of d-2-hydroxyglutarate dehydrogenase activity, proving that mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria.
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.forename: Younes
authors.initials: Y
authors.lastname: Achouri
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grosso
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000494:pharmacology*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005977:Glutarates / Q000378:metabolism / Q000652:urine*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase