title: DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria.
abstract: Abnormalities in metabolite profiles are valuable indicators of underlying pathologic conditions at the molecular level. However, their interpretation relies on detailed knowledge of the pathways, enzymes, and genes involved. Identification and characterization of their physiological function are therefore crucial for our understanding of human disease: they can provide guidance for therapeutic intervention and help us to identify suitable biomarkers for monitoring associated disorders. We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level. This disorder has been associated with varying neurological symptoms. Exome sequencing of a single affected individual revealed compound heterozygosity for an initiating methionine mutation (c.1A>G) and a missense mutation (c.2185G>A [p.Gly729Arg]) in DHTKD1. This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein. Sequence analysis of a second individual identified the same missense mutation together with a nonsense mutation (c.1228C>T [p.Arg410(∗)]) in DHTKD1. Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA. Moreover, investigation of L-lysine metabolism showed an accumulation of deuterium-labeled 2-oxoadipate only in noncomplemented cells, demonstrating that DHTKD1 codes for the enzyme mediating the last unresolved step in the L-lysine-degradation pathway. All together, our results establish mutations in DHTKD1 as a cause of human 2-aminoadipic and 2-oxoadipic aciduria via impaired turnover of decarboxylation 2-oxoadipate to glutaryl-CoA.
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Danhauser
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Christian
authors.initials: C
authors.lastname: Staufner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Thorsten
authors.initials: T
authors.lastname: Traub
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
mesh_terms: D015074:2-Aminoadipic Acid / Q000652:urine*; D000272:Adipates / Q000652:urine*; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D023061:Gene Order; D005838:Genotype; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex; D007658:Ketone Oxidoreductases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D000272:Adipates; D015074:2-Aminoadipic Acid; C001918:alpha-ketoadipic acid; D007658:Ketone Oxidoreductases; C578281:DHTKD1 protein, human; D007655:Ketoglutarate Dehydrogenase Complex