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). This complex decarboxylates ketoacid derivatives of leucine, isoleucine, and valine, thus playing a vital role in amino acid metabolism [1,2].

A Bckdhb-/-mouse model recapitulates the severe human phenotype of maple syrup urine disease (MSUD), with early-neonatal symptoms leading to death during the first week of life and massive accumulation of MSUD biomarkers [1]. In two models of severe MSUD (Bckdhb-/-mice), a one-time postnatal injection of a dual-function recombinant adeno-associated virus serotype 9 vector delivering codon-optimized BCKDHA and BCKDHB prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in multiple tissues, and stabilized MSUD biomarkers even with high protein ingestion [2].

In conclusion, Bckdhb is essential for the normal metabolism of BCAAs. The study of Bckdhb-/-mouse models has significantly advanced our understanding of the role of Bckdhb in MSUD, demonstrating its potential as a target for gene therapy in treating this inborn error of metabolism [1,2].

References:

1. Pontoizeau, Clément, Gaborit, Clovis, Tual, Nolan, Cavazzana, Marina, Schiff, Manuel. 2023. Successful treatment of severe MSUD in Bckdhb-/- mice with neonatal AAV gene therapy. In Journal of inherited metabolic disease, 47, 41-49. doi:10.1002/jimd.12604. https://pubmed.ncbi.nlm.nih.gov/36880392/

2. Wang, Jiaming, Poskitt, Laura E, Gallagher, Jillian, Strauss, Kevin A, Wang, Dan. 2025. BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease. In Science translational medicine, 17, eads0539. doi:10.1126/scitranslmed.ads0539. https://pubmed.ncbi.nlm.nih.gov/40009698/