BCKDK was first reported in relation to branched-chain keto acid dehydrogenase kinase deficiency, which is inherited in an autosomal recessive manner, in 2012 (Novarino et al, PMID 22956686). Evidence supporting this gene-disease relationship includes case-level and experimental data. Five unique variants (nonsense, frameshift, missense, and generation of a cryptic splice site) have been reported in in 8 individuals in 5 families (3 families each had 2 affected siblings) (Novarino et al, 2012, PMID 22956686; García-Cazorla et al, 2014, PMID 24449431). This gene-disease relationship is supported by the biochemical function of BCKDK, studies in fibroblasts from patients showing increased metabolism of branched chain alpha-keto acids, rescue of phosphorylation of E1-alpha in BCKDK-deficient fibroblasts upon expressing the wild type cDNA, a knock out mouse model (Joshi et al, 2006, PMID 16875466), and a natural rat model (Zigler et al, 2016, PMID 27472223). BCKDK negatively regulates the branched chain alpha-keto acid dehydrogenase (BCKD) complex by phosphorylating the E1-alpha subunit. As a result, the BCKD complex is constitutively active, resulting in the low levels of branched chain amino and alpha-keto acids observed in patients and animal models.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.