DHTKD1 Mutations Cause 2-Aminoadipic and 2-Oxoadipic Aciduria

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DHTKD1 Mutations Cause 2-Aminoadipic and 2-Oxoadipic Aciduria Katharina Danhauser, 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 The American Journal of Human Genetics Volume 91, Issue 6, Pages 1082-1087 (December 2012) DOI: 10.1016/j.ajhg.2012.10.006 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2012 91, 1082-1087DOI: (10.1016/j.ajhg.2012.10.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2012 91, 1082-1087DOI: (10.1016/j.ajhg.2012.10.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2012 91, 1082-1087DOI: (10.1016/j.ajhg.2012.10.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2012 91, 1082-1087DOI: (10.1016/j.ajhg.2012.10.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions