Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria.
We report a set of 412-year-old monozygotic (MZ) female twins with D-2-hydroxyglutaric aciduria who are shown to be compound heterozygotes for c.326-327dupTC, p.Glu110ArgfsX19, and c.1123G-->T, p.Asp375Tyr mutations in the D-2-hydroxyglutarate dehydrogenase gene, but who have remarkably different clinical phenotypes.
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.
Recently, we reported pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D-2-hydroxyglutaric aciduria in two patients.