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Case Reports
. 2012 Dec 7;91(6):1082-7.
doi: 10.1016/j.ajhg.2012.10.006. Epub 2012 Nov 8.

DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria

Katharina Danhauser  1 , Sven W Sauer, Tobias B Haack, Thomas Wieland, Christian Staufner, Elisabeth Graf, Johannes Zschocke, Tim M Strom, Thorsten Traub, Jürgen G Okun, Thomas Meitinger, Georg F Hoffmann, Holger Prokisch, Stefan Kölker
Affiliations
Case Reports

DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria

Katharina Danhauser et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Proposed Multicompartmental Degradative Pathway of L-lysine L-Lysine degradation is initiated by either peroxisomal α-deamination (pipecolate pathway) or mitochondrial ε-deamination (saccharopine pathway). Both pathways converge in 2-aminoadipate semialdehyde, which is subsequently metabolized to 2-aminoadipate and 2-oxoadipate. Our data strongly indicate that DHTKD1 is part of a 2-oxoglutarate-dehydrogenase-complex (OGDHc)-like enzyme and is involved in the decarboxylation of 2-oxoadipate to glutaryl-CoA. A minor route for this reaction via the tricarboxylic-acid (TCA)-cycle enzyme OGDHc might exist but does not compensate for the lack of DHTKD1. Succinyl-CoA and glutaryl-CoA are known to inhibit OGDHc (not shown). DTHKD1 might be an interesting drug target for glutaric aciduria type I, which is caused by inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). MIM numbers of inherited diseases of the lysine degradative pathway are provided (e.g., MIM 245130 for 2-aminoadipic and 2-oxoadipic aciduria). Dotted lines indicate multiple enzymatic steps. The following abbreviations are used: AADAT, 2-aminoadipate transaminase; AASDH, 2-aminoadipate-6-semialdehyde dehydrogenase; AASS, 2-aminoadipate-6-semialdehyde synthetase; DHTKD1, proposed E1 subunit of an OGDHc-like complex; and PIPOX, pipecolate oxidase. Mitochondrial transporters are not shown in this figure.
Figure 2
Figure 2
Pedigrees of Investigated Families and DHTKD1 Structure and Conservation of Identified Mutations (A) Mutation status of affected (closed symbols) and unaffected (open symbols) family members. (B) Structure of DHTKD1 with localization and conservation of affected amino acid residues of identified mutations.
Figure 3
Figure 3
Metabolic Function of DHTKD1 Primary fibroblasts of several controls (C) and of individuals 1 and 2, as well as fibroblasts expressing wild-type DHTKD1 from individuals 1 and 2 (1-T and 2-T, respectively) and a healthy control (C-T) were cultivated in MEM medium for 4 days. Fibroblasts from the affected individuals showed increased intracellular and extracellular levels of 2-oxoadipate. Expressions of wild-type DHTKD1 in these cells reduced intracellular and extracellular 2-oxoadipate concentrations to the levels seen in metabolically competent control fibroblasts. Data are presented as the mean of five independent experiments ± the standard deviation (∗∗p < 0.01, ∗∗∗p < 0.001). Immunoblotting of the same cell lines was performed on mitochondria-enriched samples. The antibody against DHTKD1 (Sigma-Aldrich, SAB 1400619, dilution 1:1,000) demonstrated increased levels of DHTKD1. An antibody against the complex III core protein 2 (Abcam, ab14745, dilution 1:1,000) was used as a loading control.
Figure 4
Figure 4
d4-Oxoadipate Production by Fibroblasts Several control (C) fibroblasts and fibroblasts from individuals 1 and 2 with compound heterozygous DHTKD1 mutations were cultivated in MEM medium supplemented with 4 mM 4,4,5,5-d4-lysine. Detection of d4-oxoapidate in cells and media showed an overproduction of d4-oxoadipate in fibroblasts of individuals 1 and 2; this overproduction was reduced by the expression of wild-type DHTKD1 (C-T, 1-T, and 2-T). Data are presented as the mean of four independent measurements ± the standard deviation. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
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