| DHTKD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | DHTKD1, AMOXAD, CMT2Q, dehydrogenase E1 and transketolase domain containing 1, AAKAD | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 614984 MGI: 2445096 HomoloGene: 10278 GeneCards: DHTKD1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[5]
Structure
The DHTKD1 gene encodes a protein that has 919 amino acids, and is one of two isoforms within the 2-oxoglutarate-dehydrogenase complex.[5]
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.[6] 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.[7]
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.[6][8]
Mutations in this gene could also cause neurological abnormalities.[7] 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.[6]
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000181192 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025815 - Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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. S2CID 27665973.
- ↑ 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 (5): 873–9. doi:10.1007/s10545-015-9841-9. PMID 25860818. S2CID 20379124.
Further reading
- 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. S2CID 27665973.
- Xu WY, Gu MM, Sun LH, Guo WT, Zhu HB, Ma JF, Yuan WT, Kuang Y, Ji BJ, Wu XL, Chen Y, Zhang HX, Sun FT, Huang W, Huang L, Chen SD, Wang ZG (Dec 2012). "A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree". American Journal of Human Genetics. 91 (6): 1088–94. doi:10.1016/j.ajhg.2012.09.018. PMC 3516600. PMID 23141294.
- Bunik VI, Degtyarev D (May 2008). "Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins". Proteins. 71 (2): 874–90. doi:10.1002/prot.21766. PMID 18004749. S2CID 23882203.
- 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.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.