DHTKD1

Dehydrogenase E1 and transketolase domain containing 1

Identifiers

DHTKD1 ; AMOXAD; CMT2Q

External IDs

OMIM: 614984 HomoloGene: 10278 GeneCards: DHTKD1 Gene

1.2.4.2

Gene ontology
Molecular function	• oxoglutarate dehydrogenase (succinyl-transferring) activity • thiamine pyrophosphate binding
Cellular component	• mitochondrion • cytosol • oxoglutarate dehydrogenase complex
Biological process	• hematopoietic progenitor cell differentiation • generation of precursor metabolites and energy • glycolytic process • tricarboxylic acid cycle
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 10:
12.07 – 12.12 Mb

Chr 2:
5.9 – 5.94 Mb

PubMed search

Dehydrogenase E1 and transketolase domain containing 1 is a protein that in humans is encoded by the DHTKD1 gene. This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q.^[1]

Structure

The DHTKD1 gene encodes a protein that has 919 amino acids, and is one of two isoforms within the 2-oxoglutarate-dehydrogenase complex.^[1]

Function

DHTKD1 is part of an OGDHc-like supercomplex that is responsible for a crucial step in the degradation pathways of L-lysine, L-hydroxylysine, and L-tryptophan. Specifically, this enzyme catalyzes the decarboxylation of 2-oxoadipate to glutaryl-CoA.^[2] There is a strong correlation between DHTKD1 expression levels and ATP production, which signifies that DHTKD1 plays a critical role in energy production in mitochondria. Moreover, suppression of DHTKD1 results in decreased levels of biogenesis and increased levels of reactive oxygen species (ROS) within the mitochondria. Globally, this impairs cell growth and enhances cell apoptosis.^[3]

Clinical significance

Mutations in the DHTKD1 gene are associated with alpha-aminoadipic and alpha-ketoadipic aciduria, an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. Only a handful of mutations have been observed in patients, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations are the most common cause of the deficiency. The clinical presentation of this disease in inconsistent.^[2]^[4]

Mutations in this gene could also cause neurological abnormalities.^[3] Indeed, one form of Charcot-Marie-Tooth (CMT) disease has been associated with DHTKD1, although the disease encompasses a wide spectrum of clinical neuropathies. Specifically, a hyterozygous nonsense mutation within the gene leads to decreased levels of DHTKD1 mRNA and proteins, and impaired ATP generation. This implicates this mutation as a causative agent for CMT-2 Disease.^[2]

References

1 2 "Entrez Gene: Dehydrogenase E1 and transketolase domain containing 1".
1 2 3 Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E, Zschocke J, Strom TM, Traub T, Okun JG, Meitinger T, Hoffmann GF, Prokisch H, Kölker S (Dec 2012). "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria". American Journal of Human Genetics 91 (6): 1082–7. doi:10.1016/j.ajhg.2012.10.006. PMC: 3516599. PMID 23141293.
1 2 Xu W, Zhu H, Gu M, Luo Q, Ding J, Yao Y, Chen F, Wang Z (Nov 2013). "DHTKD1 is essential for mitochondrial biogenesis and function maintenance". FEBS Letters 587 (21): 3587–92. doi:10.1016/j.febslet.2013.08.047. PMID 24076469.
↑ Hagen J, Te Brinke H, Wanders RJ, Knegt AC, Oussoren E, Hoogeboom AJ, Ruijter GJ, Becker D, Schwab KO, Franke I, Duran M, Waterham HR, Sass JO, Houten SM (Apr 2015). "Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria". Journal of Inherited Metabolic Disease 38: 873–9. doi:10.1007/s10545-015-9841-9. PMID 25860818.

DHTKD1

Structure

Function

Clinical significance

References

Further reading