Three different homozygous variants (one nonsense, one frameshift, one missense) in the BCKDK gene that segregated with disease were identified in three consanguineous families presenting with autism and ID (Novarino et al., 2012).
Molecular Function
Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex. Defects in this gene are associated with branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) [MIM:614923], a metabolic disorder characterized by autism, epilepsy, intellectual disability, and reduced branched-chain amino acids.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
A novel mutation causing a phenotype named frogleg, because its severe splaying of the hind limbs, arose spontaneously in a colony of Sprague Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated cerebral ventricles and infertility. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging.
References
Type
Title
Author, Year
Primary
A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A novel mutation arose spontaneously in a colony of Sprague Dawley rats.
Allele Type: Spontaneous mutation
Strain of Origin: Sprague Dawley
Genetic Background: Sprague Dawley
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Unreported
Description: While the appearance and size of the brains were similar, the weights of the brains from affected animals were significantly lower than those of unaffected littermates.
Exp Paradigm: General observations
Description: Decreased amplitude of sciatic muscle action potentials, marginally increased compound muscle action potential latency
Exp Paradigm: In vivo local field potential (LFP) recordings: stimulating electrode at the sciatic notch, recording electrodes in the plantar surface of the foot
Description: The male mutant rat had smaller testes than the wild type and SD rats, and histopathology revealed oligospermia with reduced and abnormal seminiferous epithelium and spermatogenesis, consistent with the clinical observation of subfertility
Exp Paradigm: Histology
Description: Hind limb musculature of mutant animals had scattered, shrunken and angular myofibers suggestive of a denervation atrophy.
Exp Paradigm: General observations
Description: Weights for mutants began to diverge from wild-type littermates at 1 week of age, and trend continued for 2-3 weeks when mutant animals averaged about 30% lower body weight. For the next 4-5 weeks both groups of pups grew at a similar rate, and the deficit gradually dimished and by about 10 weeks of age the body weights were not different.
Exp Paradigm: Body weight measurement
Description: No visible phosphorylation of BCKDH E1alpha subunit, a target of BCKDK
Exp Paradigm: Western blot: phospho-Ser293 BCKDH antibody, using anterior-posterior slices of brain tissue taken near the midline
Description: 70-80% reduction in plasma of branched-chain amino acids: leucine, isoleucine and valine, with no significant difference for any other amino acids
Exp Paradigm: Ion-exchange chromatography using a Biochrom30+ amino acid analyzer
