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.
Bckdk null mice have lower blood and tissue levels of the BCAAs. The mutant mice are 15% smaller at 12 weeks and the brain, muscle and adipose tissue weights are reduced, whereas weights of the liver and kidney are greater. Hind limb flexion is observed in the mutant mice throughout life and epileptic seizures start after 6-7 months of age. Bckdk null mice show significant improvement in growth and appearance when fed a high protein diet or BCAA-enriched diet. Bckdk nulls also exhibit defects in motor related tests, social interactions, and abnormal neurotransmission in layer 2/3 of the somatosensory cortex and cerebellar Purkinje cells.
References
Type
Title
Author, Year
Primary
Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Bckdk gene was disrupted with a gene trap vector, upstream of exon2.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: 129/SvEvBrd
Mutant ES Cell Line: Not specified
Model Source: Not specified
Description: Bckdk nulls exhibit decreased locomotor activity (decreased total distance moved and decreased mean velocity) with similar habituation time course relative to heterozygous controls
Exp Paradigm: Open field test: total distance moved and mean velocity
Description: Bckdk nulls exhibit an increase in the amplitude of mepscs
Exp Paradigm: Whole-cell patch clamp: pyramidal neurons in layer 2/3 of the somatosensory cortex
Description: Bckdk nulls exhibit a decrease in the frequency of mepscs
Exp Paradigm: Whole-cell patch clamp: pyramidal neurons in layer 2/3 of the somatosensory cortex
Description: Bckdk nulls exhibit increased incidence of epileptic seizures evoked by touching, gently hanging by tail or cage changing
Exp Paradigm: Observation of seizures: mice are held by the tail for 20 sec to determine whether a seizure will occur
Description: Increased incidence of epileptic seizures evoked by touching, gently hanging by tail or cage changing
Exp Paradigm: Observation of seizures
Description: Bckdk nulls display no preference to unfamiliar mouse over an object as wildtype controls do
Exp Paradigm: Three-chamber social approach test
Description: Abnormal developmental trajectory indicated by slower growth during week 4 but higher during weeks 5-6
Exp Paradigm: General observations; male mice
Description: Bckdk nulls have decreased tissue weights of brain, muscle and adipose relative to whole body weight
Exp Paradigm: Measurement of tissue weight
Description: Bckdk nulls have decreased body weight relative to wildtype controls, which starts from postnatal week 2
Exp Paradigm: General observations; male mice
Description: Bckdk nulls have decreased bcaa (leucine, isoleucine, and valine) concentration in blood, brain, heart, muscle, and kidney, but have no statistically significant reduction in liver
Exp Paradigm: Ion-exchange chromatography analysis of bcaa in liver, heart, kidney and muscle
Description: Bckdk nulls exhibit decreased phosphorylation of bckdha-e1a in brain despite a normal expression level of bckdha-e1a
Exp Paradigm: Western blot: bckdha-e1a
Description: Increased bckdh activity in brain, heart, muscle and kidney, which is supported by the presence of completely dephosphorylated bckdh complex in these tissues
Exp Paradigm: Spectrophotometric measurement of nadh production
Description: Bckdk nulls exhibit decreased phosphorylation of bckdha-e1a in all tissues except for liver (no change)
Exp Paradigm: Western blot: bckdha-e1a
Description: Bckdk protein is absence in bckdk nulls and about half the amount in bckdk hets relative to wildtype controls
Exp Paradigm: Western blot: bckdk
Description: Increased levels of e1alpha or e1beta subunit of bckdh (branched-chain alpha-keto acids dehydrogenase complex) in heart, kidney, muscle and brain
Exp Paradigm: Western blot: e1alpha or e1beta subunit of bckdh
