Genetic basis of alpha‐aminoadipic and alpha‐ketoadipic aciduria

Hagen, Jacob; Brinke, Heleen te; Wanders, Ronald J. A.; Knegt, Alida C.; Oussoren, Esmée; Hoogeboom, A. Jeannette M.; Ruijter, George J. G.; Becker, Daniel M.; Schwab, Karl Otfried; Franke, Ingo; Durán, Marinus; Waterham, Hans R.; Sass, Jörn Oliver; Houten, Sander M.

doi:10.1007/s10545-015-9841-9

Cited by 56 publications

(52 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The patients with variants in ARHGEF10 and IKBKAP belonged to the no/low neuropathy group, in agreement with the fact that activating rather than LOF mutations in ARHGEF10 cause CMT (46) and that no phenotype is observed for IKBKAP heterozygous individuals (47). The variant in DHTKD1 was present in two patients with different neuropathy, but recent data question the role of this gene in CMT disease (48,49). Among the remaining LOF variants, two affected EPHA genes (EPHA5 and EPHA8) and corresponded to high-neuropathy patients.…”

Section: Concerning Other Genes Potentially Associated With the Neurosupporting

confidence: 69%

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

Apellániz-Ruiz

Tejero

Inglada‐Pérez

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Translational RelevancePaclitaxel treatment frequently cause peripheral neuropathy, an adverse event that can limit treatment course and lead to permanent symptoms drastically decreasing quality of life. Our group has contributed to the identification and validation of common polymorphisms in EPHA genes associated with paclitaxel neuropathy, but a large part of the inter-individual variation in neuropathy remains unexplained. We hypothesized that low-frequency variants with strong effects may contribute to the neuropathy variability in patients. By performing targeted exon sequencing of candidate genes we found for the first time that patients carrying low-frequency non-synonymous coding variants in EPHA5/6/8 contribute to paclitaxelinduced neuropathy susceptibility. Furthermore, these genes might also be relevant neuropathy markers for other neurotoxic drugs due to the involvement of Eph receptors in neuronal functions. 4ABSTRACT Purpose: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes. were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10 -4 ). Conclusion:This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy.Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.

show abstract

Section: Concerning Other Genes Potentially Associated With the Neurosupporting

confidence: 69%

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

Apellániz-Ruiz

Tejero

Inglada‐Pérez

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Mutations in DHTKD1 lead to a defect in KADHC activity and cause α-aminoadipic and αketoadipic aciduria (Danhauser et al, 2012;Hagen et al, 2015), a condition that is currently regarded as a biochemical phenotype of questionable clinical significance, which means that it can be diagnosed through biochemical and genetic methods, but is considered not harmful (Fischer and Brown, 1980;Fischer et al, 1974;Goodman and Duran, 2014). This observation led to the hypothesis that GA1 can be treated through substrate reduction by inhibiting DHTKD1, which was speculated to divert the accumulation of neurotoxic glutaryl-CoA into less harmful accumulation of α-aminoadipic and α-ketoadipic acid.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of DHTKD1 mutations in individuals with α-aminoadipic and α-ketoadipic aciduria suggests that DHTKD1 is essential for the conversion of α-ketoadipic acid into glutaryl-CoA (Danhauser et al, 2012;Hagen et al, 2015;Stiles et al, 2016). Additional evidence was provided by the study of the BXD recombinant inbred mouse strains.…”

Section: The Hypomorphic C57bl/6 Dhtkd1 Allele Is Not Protective In Amentioning

confidence: 99%

“…In this pathway, α-ketoadipic acid (AKA) undergoes oxidative decarboxylation catalyzed by a recently discovered α-ketoadipic acid dehydrogenase complex (KADHC). The existence of this complex is based on the identification of mutations in DHTKD1 in individuals with αaminoadipic and α-ketoadipic aciduria, an established inborn error of lysine metabolism (Danhauser et al, 2012;Hagen et al, 2015;Stiles et al, 2016). DHTKD1 encodes the dehydrogenase E1 and transketolase domain-containing protein 1 (DHTKD1), a close protein homolog of OGDH, the E1 subunit of the α-ketoglutarate dehydrogenase complex (KGDHC) .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

DHTKD1 and OGDH display in vivo substrate overlap and form a hybrid ketoacid dehydrogenase complex

Leandro

Dodatko

Aten

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here we show that loss of DHTKD1 in GCDH-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine, and demonstrate that OGDH is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, DLST and DLD to form a hybrid α-ketoglutaric and α-ketoadipic acid dehydrogenase complex. In summary, α-ketoadipic acid is an in vivo substrate for DHTKD1, but also OGDH.The classic α-ketoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards α-ketoadipic acid.

show abstract

“…2-Aminoadipic and 2-oxoadipic aciduria (OMIM 204750) is an inborn error of metabolism with questionable clinical consequence [20], characterized biochemically by increased urinary excretion of 2-oxoadipate and its transamination product 2-aminoadipate [21,22]. Among < 30 reported cases due to autosomal recessive missense and nonsense mutations [23], p.Gly729Arg and p.Arg455Gln are common variants. Additionally, a nonsense DHTKD1 mutation causes Charcot-Marie-Tooth disease type 2Q (CMT2Q, OMIM 615025), an autosomal dominant neurodegenerative disorder characterized by motor and sensory neuropathies [24].…”

Section: Introductionmentioning

confidence: 99%

Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism

Bezerra

Foster

Bailey

et al. 2020

Preprint

View full text Add to dashboard Cite

DHTKD1 is a lesser-studied E1 enzyme belonging to the family of 2-oxoacid dehydrogenases.DHTKD1, in complex with the E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (lipoamide dehydrogenase, DLD) components, is implicated in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in the mitochondria. Here, we solved the crystal structure of human DHTKD1 at 1.9 Å resolution in binary complex with the thiamine diphosphate (ThDP) cofactor. Our structure explains the evolutionary divergence of DHTKD1 from the well-characterized homologue 2-oxoglutarate (2OG) dehydrogenase, in its preference for the larger 2OA substrate than 2OG. Inherited DHTKD1 missense mutations cause the lysine metabolic condition 2-aminoadipic and 2-oxoadipic aciduria. Reconstruction of the missense variant proteins reveal their underlying molecular defects, which include protein destabilisation, disruption of protein-protein interactions, and alterations in the protein surface.We further generated a 5.0 Å reconstruction of the human DLST inner core by single-particle electron microscopy, revealing a 24-mer cubic architecture that serves as a scaffold for assembly of DHTKD1 and DLD. This structural study provides a starting point to develop small molecule DHTKD1 inhibitors for probing mitochondrial energy metabolism. KEYWORDS 2-oxoadipate, 2-oxoacid dehydrogenase, thiamine diphosphate, lysine catabolism, missense variants, x-ray crystallography, electron microscopy

show abstract

Genetic basis of alpha‐aminoadipic and alpha‐ketoadipic aciduria

Cited by 56 publications

References 29 publications

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

DHTKD1 and OGDH display in vivo substrate overlap and form a hybrid ketoacid dehydrogenase complex

Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism

Contact Info

Product

Resources

About