Bckdhb, encoding the E1β subunit of the mitochondrial branched-chain 2-ketoacid dehydrogenase (BCKD) enzyme complex, is crucial for the catabolism of branched-chain amino acids (BCAAs) [1,2]. The BCKD complex decarboxylates ketoacid derivatives of leucine, isoleucine, and valine, thus playing a key role in amino acid metabolism pathways [2].

In a Bckdhb-/-mouse model, which recapitulates the severe human phenotype of maple syrup urine disease (MSUD), early-neonatal symptoms occur leading to death within the first week of life with massive accumulation of MSUD biomarkers [1]. This indicates that Bckdhb is essential for normal metabolism and survival, as its loss leads to the characteristic MSUD-associated metabolic derangements. Additionally, gene therapy in Bckdhb-/-mice using an AAV8-capsid-encapsulated transgene carrying the human BCKDHB gene under the control of a ubiquitous EF1α promoter achieved long-term rescue of the severe MSUD phenotype [1]. Also, a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector delivering codon-optimized BCKDHA and BCKDHB restored co-expression of the two genes, BCKDH holoenzyme activity, and normalized growth and MSUD biomarkers in Bckdhb-/-mice [2].

In conclusion, Bckdhb is essential for the normal catabolism of BCAAs through its role in the BCKD enzyme complex. The study of Bckdhb-/-mouse models has significantly advanced our understanding of its function and its critical role in MSUD, a rare autosomal recessive metabolic disorder. These models have also demonstrated the potential of gene therapy approaches targeting Bckdhb for the treatment of MSUD [1,2].