BCKDK loss-of-function mutations do not phosphorylate BCKDH

Stable Identifier
R-HSA-9912480
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
BCKDK loss-of-function mutations do not phosphorylate BCKDH
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Mutations in branched-chain ketoacid dehydrogenase kinase (BCKDK) that disrupt the dimer interface and/or destabilize the protein prevent the inhibitory phosphorylation of the E1 subunit of BCKDH, allowing unregulated oxidative decarboxylation of branched-chain amino acids. This causes a depletion of the essential amino acids and is associated with a disorder known as BCKDK deficiency, characterized by neurological delays, autism, and microencephaly (Novarino et al, 2012; Garcia-Cazorla et al, 2014; Tangeraas et al, 2023). The following mutations in BCKDK have been identified in patients showing clinical symptoms of BCKDK deficiency, sexhibit decreased kinase activity and reduced or absent levels of phosphorylated substrate BCKDHA: R156*, R224P (Novarino et al, 2012; both designated "pathogenic" or "likely pathogenic" in ClinVar); L389P, R174Gfs1* (Garcia-Carzola et al, 2014; no ClinVar pathogenicity designations).
Literature References
PubMed ID Title Journal Year
24449431 Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients

Sanz, P, Castejón, E, Nunes, V, Ruiz-Sala, P, Agulló, SB, Palacin, M, Vilaseca, MA, Robles, C, Rodríguez-Pombo, P, Ugarte, M, Lopez-Sala, A, Fort, J, Pristoupilova, A, Dopazo, J, Bodoy, S, Ormaizabal, A, Artuch, R, Garcia-Cazorla, A, Navarrete, R, Font-Llitjós, M, Alcaide, P, Merinero, B, Oyarzabal, A

Hum. Mutat. 2014
36729635 BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening

Ozturk-Hism, B, Constante, JR, Martinez, C, Machado, I, Debray, FG, Ummuhan, O, Backe, PH, Pajares, S, Stoway, SD, Mørkrid, L, Footitt, E, Ozturkmen-Akay, H, De Los Santos, M, López, JM, Boemer, F, Ormazabal, A, Davison, J, Karaca, M, Evren, G, Dixon, M, Tuba, EF, Al-Sannaa, N, Weinhold, N, Bueno, C, Neugebauer, J, García-Cazorla, A, Tangeraas, T, Rodríguez-Pombo, P, Tekin, M, Artuch, R, Oyarzabal, A

Brain 2023
22956686 Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy

Khalil, RO, Harris, RA, Ben-Omran, T, State, MW, Gleeson, JG, Hashish, AF, El-Fishawy, P, Schroth, J, Novarino, G, Scott, EM, Meguid, NA, Ercan-Sencicek, AG, Gabriel, S, Sanders, SJ, Matern, D, Hashem, HS, Kara, M, Kayserili, H, Sweetman, L, Gupta, AR, Rahimi, Y, Silhavy, JL

Science 2012
Participants
Input
Participates
as an event of
Catalyst Activity

[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity of BCKDK mutant dimers [mitochondrial matrix]

Physical Entity
BCKDK mutant dimers [mitochondrial matrix] (Homo sapiens)
Activity
[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity (GO:0047323)
Normal reaction
BCKDK phosphorylates BCKDH (Homo sapiens)
Functional status

Loss of function of BCKDK mutant dimers [mitochondrial matrix]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
branched-chain keto acid dehydrogenase kinase deficiency DOID:0090126 BCKDKD, BCKDK deficiency, autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-06-08)
Cite Us!