Alternative titles; symbols
HGNC Approved Gene Symbol: BCAT2
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,795,064-48,811,029 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | ?Hypervalinemia or hyperleucine-isoleucinemia | 618850 | Autosomal recessive | 3 |
The BCAT2 gene encodes the mitochondrial isoform of the branched-chain amino acid (BCAA) aminotransferase (BCAT), which catalyzes the transamination of the branched-chain amino acids (leucine, isoleucine, and valine) to their respective alpha-keto acids in the first step of BCAA catabolism (summary by Wang et al., 2015).
Eden et al. (1996) characterized the BCAT2 gene in human and yeast and demonstrated that the yeast homologs of Bcat1 (113520) and Bcat2 code for cytosolic and mitochondrial enzymes, respectively.
By study of somatic cell hybrids, Naylor and Shows (1979, 1980) assigned the gene for BCT2 to chromosome 19.
Bassett et al. (1997) mapped the mouse Bcat2 gene to chromosome 7 as part of the XREF project. On the basis of the conserved synteny between mouse and human chromosomes, Ben-Yosef et al. (1998) suggested that the human BCAT2 gene maps to 19q13.
In a patient with remarkably elevated plasma valine and leucine concentrations (HVLI; 618850), Wang et al. (2015) identified compound heterozygous missense mutations in the BCAT2 gene (R170Q, 113530.0001; E264K, 113530.0002). Expression of purified recombinant BCAT2 carrying each mutation showed diminished enzyme activity of less than 50% of wildtype protein in each case. No direct measure of enzyme activity was reported in patient cells. Hamosh (2020) commented that while, per the gnomAD database, the BCAT2 gene is tolerant of variation, this finding is not surprising for an enzyme-encoding gene and for recessive inheritance. Nevertheless, there were very few variants found in homozygosity (April 20, 2020).
In a large N-ethyl-N-nitrosourea (ENU)-induced mouse mutagenesis program, Wu et al. (2004) identified a phenotype characterized by striking elevation of serum branched-chain amino acids and a moderate increase in arginine. Clinically, the affected mice also showed failure to thrive, weakness, decreased spontaneous movement, and thin hair, features seen in humans with maple syrup urine disease (248600). In the affected mice, Wu et al. (2004) identified a homozygous T-to-C transition in the 5-prime splicing site consensus sequence of exon 2 and intron 2 of the Bcat2 gene, resulting in deletion of exon 2. RT-PCR showed markedly reduced amounts of Bcat2 mRNA in muscle and liver compared to controls. The authors noted that exon 2 contains the mitochondrial targeting leader sequence. A diet low in branched-chain amino acids resulted in clinical improvement in the mice.
In a 25-year-old man with hypervalinemia and hyperleucine-isoleucinemia (HVLI; 618850), Wang et al. (2015) reported compound heterozygosity for a c.509G-A transition in the BCAT2 gene resulting in an arg170-to-gln substitution (R170Q), and a c.790G-A transition resulting in a glu264-to-lys substitution (E264K). The R170Q mutation had been inherited from his father and E264K from his mother. Hamosh (2020) noted that the R170Q mutation was present in 1 of 250,096 alleles, and the E264K mutation in heterozygosity in 3 of 250,338 alleles, in the gnomAD database (April 20, 2020).
For discussion of the glu264-to-lys mutation (E264K) in the BCAT2 gene that was found in compound heterozygous state in a patient with hypervalinemia and hyperleucine-isoleucinemia (HVLI; 618850) by Wang et al. (2015), see 113530.0001.
Bassett, D. E., Jr., Boguski, M. S., Spencer, F., Reeves, R., Kim, S., Weaver, T., Hieter, P. Genome cross-referencing and XREFdb: implications for the identification and analysis of genes mutated in human disease. Nature Genet. 15: 339-344, 1997. [PubMed: 9090377] [Full Text: https://doi.org/10.1038/ng0497-339]
Ben-Yosef, T., Eden, A., Benvenisty, N. Characterization of murine BCAT genes: Bcat1, a c-Myc target, and its homolog, Bcat2. Mammalian Genome 9: 595-597, 1998. [PubMed: 9657861] [Full Text: https://doi.org/10.1007/s003359900825]
Eden, A., Simchen, G., Benvenisty, N. Two yeast homologs of ECA39, a target for c-Myc regulation, code for cytosolic and mitochondrial branched-chain amino acid aminotransferases. J. Biol. Chem. 271: 20242-20245, 1996. [PubMed: 8702755] [Full Text: https://doi.org/10.1074/jbc.271.34.20242]
Hamosh, A. Personal Communication. Baltimore, Md. 04/20/2020.
Naylor, S. L., Shows, T. B. Branched-chain aminotransferase genes (BCT-1 and BCT-2) assigned to human chromosomes 12 and 19 using alpha-keto acid selection media. (Abstract) Cytogenet. Cell Genet. 25: 191-192, 1979.
Naylor, S. L., Shows, T. B. Branched-chain aminotransferase deficiency in Chinese hamster cells complemented by two independent genes on human chromosomes 12 and 19. Somat. Cell Genet. 6: 641-652, 1980. [PubMed: 6933702] [Full Text: https://doi.org/10.1007/BF01538643]
Wang, X. L., Li, C. J., Xing, Y., Yang, Y. H., Jia, J. P. Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J. Inherit. Metab. Dis. 38: 855-861, 2015. [PubMed: 25653144] [Full Text: https://doi.org/10.1007/s10545-015-9814-z]
Wu, J.-Y., Kao, H.-J., Li, S.-C., Stevens, R., Hillman, S., Millington, D., Chen, Y.-T. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease. J. Clin. Invest. 113: 434-440, 2004. [PubMed: 14755340] [Full Text: https://doi.org/10.1172/JCI19574]