Format

Send to

Choose Destination
See comment in PubMed Commons below
Biochim Biophys Acta. 2017 May 22. pii: S0925-4439(17)30155-2. doi: 10.1016/j.bbadis.2017.05.018. [Epub ahead of print]

Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism.

Author information

1
Institute of Human Genetics, Technical University Munich, Trogerstr. 32, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
2
University Hospital Heidelberg, Centre for Child and Adolescent Medicine, Division of Neuropediatrics and Metabolic Medicine, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany.
3
Institute of Human Genetics, Technical University Munich, Trogerstr. 32, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
4
Institute of Human Genetics, Helmholtz Zentrum Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
5
Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
6
University Hospital Heidelberg, Centre for Child and Adolescent Medicine, Division of Neuropediatrics and Metabolic Medicine, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany. Electronic address: Sven.Sauer@med.uni-heidelberg.de.
7
Institute of Human Genetics, Technical University Munich, Trogerstr. 32, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. Electronic address: prokisch@helmholtz-muenchen.de.

Abstract

Glutaric aciduria type I (GA-I) is a rare organic aciduria caused by the autosomal recessive inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). GCDH deficiency leads to disruption of L-lysine degradation with characteristic accumulation of glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, 3-hydroxyglutaric acid (3-OHGA). DHTKD1 acts upstream of GCDH, and its deficiency leads to none or often mild clinical phenotype in humans, 2-aminoadipic 2-oxoadipic aciduria. We hypothesized that inhibition of DHTKD1 may prevent the accumulation of neurotoxic dicarboxylic metabolites suggesting DHTKD1 inhibition as a possible treatment strategy for GA-I. In order to validate this hypothesis we took advantage of an existing GA-I (Gcdh-/-) mouse model and established a Dhtkd1 deficient mouse model. Both models reproduced the biochemical and clinical phenotype observed in patients. Under challenging conditions of a high lysine diet, only Gcdh-/- mice but not Dhtkd1-/- mice developed clinical symptoms such as lethargic behaviour and weight loss. However, the genetic Dhtkd1 inhibition in Dhtkd1-/-/Gcdh-/- mice could not rescue the GA-I phenotype. Biochemical results confirm this finding with double knockout mice showing similar metabolite accumulations as Gcdh-/- mice with high GA in brain and liver. This suggests that DHTKD1 inhibition alone is not sufficient to treat GA-I, but instead a more complex strategy is needed. Our data highlights the many unresolved questions within the L-lysine degradation pathway and provides evidence for a so far unknown mechanism leading to glutaryl-CoA.

KEYWORDS:

2-aminoadipic 2-oxoadipic aciduria; DHTKD1; GCDH; Glutaric Aciduria Type I; L-Lysine; glutaric acid

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center