TY - JOUR
T1 - DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria
AU - Danhauser, Katharina
AU - Sauer, Sven W.
AU - Haack, Tobias B.
AU - Wieland, Thomas
AU - Staufner, Christian
AU - Graf, Elisabeth
AU - Zschocke, Johannes
AU - Strom, Tim M.
AU - Traub, Thorsten
AU - Okun, Jürgen G.
AU - Meitinger, Thomas
AU - Hoffmann, Georg F.
AU - Prokisch, Holger
AU - Kölker, Stefan
N1 - Funding Information:
We thank the affected individuals and their families for participation in the study. We acknowledge the technical support of Evelyn Botz and Carola Fischer. T.M. and H.P. were supported by the Systems Biology of Metabotypes grant (SysMBo 0315494A) funded by the German Federal Ministry of Education and Research, the German Network for Mitochondrial Disorders (mitoNET 01GM1113c), and the E-Rare project GENOMIT (01GM1207). T.M. and T.M.S. were supported by the European Commission 7 th Framework Program (N. 261123), the Genetic European Variation in Disease Consortium, and the German Ministry for Education and Research (01GR0804-4).
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.Arg410lowast]) 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.
AB - 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.Arg410lowast]) 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.
UR - http://www.scopus.com/inward/record.url?scp=84870934078&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.10.006
DO - 10.1016/j.ajhg.2012.10.006
M3 - Article
C2 - 23141293
AN - SCOPUS:84870934078
SN - 0002-9297
VL - 91
SP - 1082
EP - 1087
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -