Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria.
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.
Struys
Eduard A
EA
Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.
Salomons
Gajja S
GS
Achouri
Younes
Y
Van Schaftingen
Emile
E
Grosso
Salvatore
S
Craigen
William J
WJ
Verhoeven
Nanda M
NM
Jakobs
Cornelis
C
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
D005977:Glutarates; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase