Alternative titles; symbols
HGNC Approved Gene Symbol: BCKDHB
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38) : 6:80,106,610-80,466,676 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.1 | Maple syrup urine disease, type Ib | 620698 | Autosomal recessive | 3 |
The second major step in the catabolism of the branched-chain amino acids, isoleucine, leucine, and valine, is catalyzed by the branched-chain alpha-keto acid dehydrogenase complex (BCKD; EC 1.2.4.4), an inner-mitochondrial enzyme complex that consists of 3 catalytic components: a heterotetrameric (alpha2, beta2) branched-chain alpha-keto acid decarboxylase (E1), a homo-24-meric dihydrolipoyl transacylase (E2; 248610), and a homodimeric dihydrolipoamide dehydrogenase (E3; 238331). The reaction is irreversible and constitutes the first committed step in BCAA oxidation. The complex also contains 2 regulatory enzymes, a kinase and a phosphorylase.
The BCKDHB gene encodes the beta subunit of E1, and the BCKDHA gene (608348) encodes the alpha subunit of E1.
Nobukuni et al. (1990) isolated and characterized a cDNA clone corresponding to the entire precursor of the BCKDHB gene from a human placental cDNA library. The cDNA encodes a mature 342-amino acid subunit with a molecular mass of 37.6 kD. The beta subunit is synthesized as a precursor with a leader sequence of 50 amino acids. Its primary structure shows strong homology to the structure of the bovine enzyme and to that of the E1-beta subunit of the human PDH complex (179060). By Northern blot analysis, Chuang et al. (1990) detected a 1.4-kb mRNA transcript for the E1-beta subunit.
Mitsubuchi et al. (1991) found that the BCKDHB gene contains 10 exons. Chuang et al. (1996) determined that the BCKDHB gene contains 11 exons.
By analysis of somatic cell hybrids, Mitsubuchi et al. (1991) mapped the BCKDHB gene to chromosome 6. By in situ hybridization, Zneimer et al. (1991) localized the BCKDHB gene to 6p22-p21. Based on sequence analysis, Edelmann et al. (2001) localized the BCKDHB gene to 6q14.
In a patient with classic maple syrup urine disease (MSUD1B; 620698), Nobukuni et al. (1991) identified a homozygous 11-bp deletion in exon 1 of the E1-beta gene (248611.0001).
Patel and Harris (1995) provided a diagram of 2 point mutations, 2 small deletions, and 1 small insertion that had been reported in the BCKDHB gene.
Edelmann et al. (2001) noted that approximately 33% (10 of 34) of families with MSUD followed in their clinic in New York were of Ashkenazi Jewish descent, leading them to search for a common mutation within this group. Three novel mutations in the BCKDHB gene were identified in 7 unrelated affected Ashkenazi Jewish patients. Six of the 7 had the same mutation (R183P; 248611.0002). The locations of the affected residues in the crystal structure of the E1-beta subunit suggested possible mechanisms for the deleterious effects of these mutations. Large-scale population screening of Ashkenazi Jewish individuals for the R183P mutation revealed that the carrier frequency of the mutant allele was approximately 1 in 113 persons; the 1 patient not carrying R183P had a previously described homozygous mutation in the gene encoding the E2 subunit (248610.0009).
In 3 unrelated Israeli patients with classic MSUD, Chuang et al. (2004) identified homozygous or compound heterozygous mutations in the BCKDHB gene (248611.0003-248611.0006). Functional expression studies in E. coli showed that the different mutations had variable expression but no residual enzyme activity.
In a patient with classic maple syrup urine disease type IB (MSUD1B; 620698), Nobukuni et al. (1991) identified a homozygous 11-bp deletion in exon 1 of the E1-beta gene, within the mitochondrial targeting peptide. Both parents were heterozygous for the mutation, whereas an affected brother and a sister were homozygous. The absence of the E1-beta subunit resulted in instability of the E1-alpha subunit.
In Ashkenazi Jewish patients with classic maple syrup urine disease type IB (MSUD1B; 620698), Edelmann et al. (2001) identified homozygosity for a 538G-C change in exon 5 of the BCKDHB gene, resulting in an arg183-to-pro (R183P) substitution. the mutation was detected in 10 of 12 chromosomes screened. The mutation is predicted to induce a structural change in the protein and impair proper folding. Two other Ashkenazi Jewish patients were compound heterozygous for the R183P mutation and another BCKDHB mutation.
In an Israeli patient with classic maple syrup urine disease (MSUD1B; 620698), Chuang et al. (2004) identified a homozygous C-to-T transition in the BCKDHB gene, resulting in a his156-to-tyr (H156Y) substitution. Expression studies of the mutant protein in E. coli showed that the H156Y protein was expressed at much lower levels compared to control (18%) and formed multiple species ranging from heterodimers to heterotetramers, reflecting an assembly defect. There was no residual enzyme activity and severely reduced affinity for the thiamine cofactor.
In an Israeli patient with classic maple syrup urine disease (MSUD1B; 620698), Chuang et al. (2004) identified a homozygous T-to-G transversion in the BCKDHB gene, resulting in a val69-to-gly (V69G) substitution. Functional expression studies in E. coli showed that the V69G mutant protein was not expressed, likely due to protein misfolding.
In an Israeli patient with classic maple syrup urine disease (MSUD1B; 620698), Chuang et al. (2004) identified compound heterozygosity for 2 mutations in the BCKDHB gene: a 4-bp deletion in intron 9 resulting in the deletion of exon 10, and an 8-bp insertion in exon 10 (248611.0006) resulting in a frameshift. There was no residual enzyme activity for either mutant protein.
For discussion of the 8-bp insertion in the BCKDHB gene that was found in compound heterozygous state in a patient with classic maple syrup urine disease (MSUD1B; 620698) by Chuang et al. (2004), see 248611.0005.
Chuang, J. L., Cox, R. P., Chuang, D. T. Molecular cloning of the mature E1b-beta subunit of human branched-chain alpha-keto acid dehydrogenase complex. FEBS Lett. 262: 305-309, 1990. [PubMed: 2335211] [Full Text: https://doi.org/10.1016/0014-5793(90)80215-5]
Chuang, J. L., Cox, R. P., Chuang, D. T. Maple syrup urine disease: the E1beta gene of human branched-chain alpha-ketoacid dehydrogenase complex has 11 rather than 10 exons, and the 3-prime UTR in one of the two E1-beta mRNAs arises from intronic sequences. Am. J. Hum. Genet. 58: 1373-1377, 1996. [PubMed: 8651316]
Chuang, J. L., Wynn, R. M., Moss, C. C., Song, J., Li, J., Awad, N., Mandel, H., Chuang, D. T. Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients. J. Biol. Chem. 279: 17792-17800, 2004. [PubMed: 14742428] [Full Text: https://doi.org/10.1074/jbc.M313879200]
Edelmann, L., Wasserstein, M. P., Kornreich, R., Sansaricq, C., Snyderman, S. E., Diaz, G. A. Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am. J. Hum. Genet. 69: 863-868, 2001. [PubMed: 11509994] [Full Text: https://doi.org/10.1086/323677]
Mitsubuchi, H., Nobukuni, Y., Endo, F., Matsuda, I. Structural organization and chromosomal localization of the gene for the E1-beta subunit of human branched chain alpha-keto acid dehydrogenase. J. Biol. Chem. 266: 14686-14691, 1991. [PubMed: 1860867]
Nobukuni, Y., Mitsubuchi, H., Akaboshi, I., Indo, Y., Endo, F., Yoshioka, A., Matsuda, I. Maple syrup urine disease: complete defect of the E1-beta subunit of the branched chain alpha-ketoacid dehydrogenase complex due to a deletion of an 11-bp repeat sequence which encodes a mitochondrial targeting leader peptide in a family with the disease. J. Clin. Invest. 87: 1862-1866, 1991. [PubMed: 2022752] [Full Text: https://doi.org/10.1172/JCI115209]
Nobukuni, Y., Mitsubuchi, H., Endo, F., Akaboshi, I., Asaka, J., Matsuda, I. Maple syrup urine disease: complete primary structure of the E1-beta subunit of human branched-chain alpha-ketoacid dehydrogenase complex deduced from the nucleotide sequence and a gene analysis of patients with this disease. J. Clin. Invest. 86: 242-247, 1990. [PubMed: 2365818] [Full Text: https://doi.org/10.1172/JCI114690]
Patel, M. S., Harris, R. A. Mammalian alpha-keto acid dehydrogenase complexes: gene regulation and genetic defects. FASEB J. 9: 1164-1172, 1995. [PubMed: 7672509] [Full Text: https://doi.org/10.1096/fasebj.9.12.7672509]
Zneimer, S. M., Lau, K. S., Eddy, R. L., Shows, T. B., Chuang, J. L., Chuang, D. T., Cox, R. P. Regional assignment of two genes of the human branched-chain alpha-keto acid dehydrogenase complex: the E1-beta gene (BCKDHB) to chromosome 6p21-22 and the E2 gene (DBT) to chromosome 1p31. Genomics 10: 740-747, 1991. [PubMed: 1889817] [Full Text: https://doi.org/10.1016/0888-7543(91)90458-q]