Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria

Am J Hum Genet. 2005 Feb;76(2):358-60. doi: 10.1086/427890. Epub 2004 Dec 17.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics*
  • Alcohol Oxidoreductases / pharmacology*
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Glutarates / metabolism
  • Glutarates / urine*
  • Humans
  • Male
  • Mutation, Missense
  • Phenotype

Substances

  • Glutarates
  • alpha-hydroxyglutarate
  • Alcohol Oxidoreductases
  • 2-hydroxyglutarate dehydrogenase