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.

Figure 1

Schematic presentation of the d-2-hydroxyglutarate dehydrogenase gene, showing exons (numbered blackened boxes) and introns (see Genbank for genomic DNA [accession number 27465811] and cDNA [accession number 22477763]). The three pathogenic mutations that were found in two patients affected with d-2-HGA are shown. The IVS1-23A→G mutation creates an alternative splice-acceptor site located 19 nt upstream of the wild-type splice-acceptor site (r.295_296ins19). Figure is drawn to scale.