Alternative titles; symbols
HGNC Approved Gene Symbol: DBT
Cytogenetic location: 1p21.2 Genomic coordinates (GRCh38): 1:100,186,919-100,249,834 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p21.2 | Maple syrup urine disease, type II | 620699 | 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-ketoacid decarboxylase (E1-alpha; 608348 and E1-beta; 248611), a homo-24-meric dihydrolipoyl transacylase (E2), 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 DBT gene encodes the E2 component.
Litwer and Danner (1985), Hummel et al. (1988), and Lau et al. (1988) reported partial cloning of the DBT gene. Analysis of the deduced protein structure showed similarities to the acyltransferase proteins of the pyruvate and alpha-ketoglutarate dehydrogenase complexes (Hummel et al., 1988).
Danner et al. (1989) isolated cDNAs encoding the carboxyl terminal of E2 and constructed a cDNA which encodes the entire precursor molecule, a 477-amino acid protein with a molecular mass of 57 kD. Mouse liver mitochondria imported and processed the protein to a 52-kD protein. Nobukuni et al. (1989) isolated a cDNA clone for the human E2 precursor from a placenta cDNA library. They found that the deduced mature human protein contains 421 amino acids and has a molecular mass of 46 kD. The deduced protein contains a leader peptide of 56 amino acids, a lipoyl-bearing domain, an E3-binding domain, and an inner core domain, connected by flexible hinge regions (see also Lau et al., 1992).
Mersey et al. (2005) demonstrated that the microRNA MIRN29B1 (610783) is targeted to DBT mRNA and prevents translation when bound in HEK293 cells. This was the first demonstration of the use of a microRNA to exert control on a metabolic pathway of amino acid catabolism in mammals, and offers an explanation for the observed differences in the amount of the BCKD complex present in different tissues and under varying nutritional states.
Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mitochondrial DNA (mtDNA) genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that DBT was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that DBT copurified with mtDNA and was a core nucleoid protein.
Lau et al. (1992) determined that the DBT gene contains 11 exons.
Using somatic cells hybrids, Herring et al. (1991) and Lau et al. (1991) mapped the E2 gene to chromosome 1. Additional data with 2 hybrids containing fragments of chromosome 1 suggested that the gene is located on the short arm in region 1pter-p21. By in situ hybridization, Zneimer et al. (1991) regionalized the assignment to 1p31.
Pseudogene
Chuang et al. (1991) characterized an E2 pseudogene which they mapped to 3q24 by in situ hybridization.
In a case of classic maple syrup urine disease (MSUD2; 620699), Herring et al. (1991) identified a 124-bp deletion in the DBT gene (248610.0001).
In a cell line from a patient with thiamine-responsive MSUD2, Fisher et al. (1991) identified compound heterozygosity for mutations in the DBT gene (248610.0002 and 248610.0003).
In several Japanese patients with the intermediate form of maple syrup urine disease, Tsuruta et al. (1998) identified homozygosity or compound heterozygosity for mutations in the DBT gene (248610.0005-248610.0008).
Patel and Harris (1995) provided diagrams of the location of 4 substitution mutations, 4 small deletions, and 1 small insertion that had been reported in the DBT gene.
Chuang et al. (1997) described 5 new mutations in the E2 gene causing both classic and intermediate/thiamine-responsive MSUD2. Several of these mutations involved rare deletions of internal intronic segments that led to secondary insertions/deletions in the transcript through utilization of cryptic or new splice sites. A 3.2-kb internal deletion in intron 4 was detected by amplification and analysis of the entire intron (normal size, 11.2 kb). Chuang et al. (1997) emphasized that no loci other than E2 of the BCKD complex have been identified in documented thiamine-responsive patients. The findings strongly suggested that a normal E1 component is a prerequisite for the thiamine-responsive phenotype.
Lebo et al. (2000) studied a child with MSUD2 who was found to be homozygous for a 10-bp deletion of the DBT gene. Neither of the purported parents carried the gene deletion. Polymorphic simple-sequence repeat analysis at 15 loci on chromosome 1 and at 16 loci on other chromosomes confirmed parentage and revealed that a de novo mutation prior to maternal meiosis I, followed by nondisjunction in maternal meiosis II, resulted in an oocyte with 2 copies of the de novo mutant allele. Fertilization by a sperm that did not carry a paternal chromosome 1 or subsequent mitotic loss of the paternal chromosome 1 resulted in the propositus inheriting 2 mutant DBT alleles on 2 maternal number 1 chromosomes.
In a case of classic maple syrup urine disease type II (MSUD2; 620699) identified by newborn screening, Herring et al. (1991) identified compound heterozygosity for mutations in the DBT gene. One allele, inherited from the father, produced transcripts with 124 nucleotides deleted from the coding region, while a nonexpressing allele, inherited from the mother, resulted in cells containing 50% of the normal amount of E2 mRNA. A phenotypically normal sib was genetically similar to the mother, having inherited the mother's nonexpressing allele and the father's normal allele.
In a cell line from a patient with thiamine-responsive maple syrup urine disease type II (MSUD2; 620699), Fisher et al. (1991) identified compound heterozygosity for mutations in the DBT gene: a T-G change, resulting in a phe215-to-cys (F215C) substitution, and a 17-bp insertion (248610.0003) apparently resulting from aberrant splicing.
For discussion of the 17-bp insertion in the DBT gene that was found in compound heterozygous state in a cell line from a patient with thiamine-responsive maple syrup urine disease type II (MSUD2; 620699) by Chuang et al. (1991), see 248610.0002.
In a patient with classic maple syrup urine disease type II (MSUD2; 620699), Mitsubuchi et al. (1991) identified homozygosity for a 78-bp deletion in the E2 gene. The consanguineous parents and an unaffected sister were heterozygous for the deletion. Analysis of genomic DNA showed that the 78-bp deletion in the mRNA was caused by an exon skipping due to a single base deletion in an intronic 5-prime splice donor site. As a result, part of the inner E2 core domain was omitted. The authors noted that this region is highly homologous to the corresponding region of the E2 subunit of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. The findings indicated the biologic importance of the inner E2 core domain.
In a Japanese patient with the intermediate form of maple syrup urine disease type II (MSUD2; 620699), Tsuruta et al. (1998) identified homozygosity for a single base substitution in intron 8, creating a new 5-prime splice site, and causing an insertion of 126 basepairs between exons 8 and 9 in the mRNA. The predicted mRNA encoded a truncated protein with 282 amino acids, including 4 novel amino acids at the carboxyl terminus.
In a Japanese patient with the intermediate form of maple syrup urine disease type II (MSUD2; 620699), Tsuruta et al. (1998) identified homozygosity for a 1463G-T transversion in exon 11 of the DBT gene, resulting in a ter422-to-leu (X422L) substitution. The mutation was predicted to add 7 amino acids at the carboxyl terminus of the E2 protein. The consanguineous parents were heterozygous for the mutation.
In a Japanese patient with the intermediate form of maple syrup urine disease type II (MSUD2; 620699), Tsuruta et al. (1998) described compound heterozygosity for a 309C-G transversion at nucleotide 309 in exon 4 of the DBT gene, and a 1165G-A transition in exon 9, resulting in an ile37-to-met (I37M) substitution and a gly323-to-ser (G323S) substitution (248610.0008), respectively.
For discussion of the gly323-to-ser (G323S) mutation in the DBT gene that was found in a patient with the intermediate form of maple syrup urine disease type II (MSUD2; 620699) by Tsuruta et al. (1998), see 248610.0007.
In several patients with classic maple syrup urine disease type II (MSUD2; 620699), Fisher et al. (1993) identified a 2-bp (AT) deletion in exon 2 of the DBT gene, causing a frameshift downstream of residue -26 in the mitochondrial targeting presequence. The mutation occurred in homozygous and compound heterozygous states.
In 2 unrelated children with classic maple syrup urine disease type II (MSUD2; 620699), Chi et al. (2003) identified a homozygous 4.7-kb deletion in the DBT gene. The deletion includes the 3-prime half of intron 10, the entire coding region of the terminal exon 11, and the 5-prime part of the 3-prime UTR of the E2 gene. Further analysis showed that the deletion resulted from a rare nonhomologous recombination of the long interspersed nuclear element-1 (LINE-1) in intron 10 and an Alu sequence in the 3-prime UTR. A third unrelated affected patient was compound heterozygous for the 4.7-kb deletion and a 2-bp deletion (248610.0009). All 3 children belonged to the Paiwan aboriginal tribe in Taiwan. The finding of the 4.7-kb deletion in 5 of 6 alleles suggested a founder effect in this population. Carrier frequency was determined to be 1 in 101 Paiwanese.
In 2 sibs, born of consanguineous parents of Arab descent, with thiamine-responsive maple syrup urine disease type II (MSUD2; 620699), Chuang et al. (2004) identified a homozygous A-to-G transition in the DBT gene, resulting in a his391-to-arg (H391R) substitution. A full-length mutant protein was expressed and resulted in increased E1 (see 608468) activity, but impaired E2-mediated acyltransferase activity. Both patients presented with neonatal encephalopathy, which was completely eradicated with thiamine supplementation and a restrictive diet.
In 2 patients from the Druze kindred in Israel with classic maple syrup urine disease type II (MSUD2; 620699), Chuang et al. (2004) identified a homozygous C-to-G transversion in the DBT gene, resulting in a ser133-to-ter (S133X) substitution. Both patients had a turbulent neonatal course with mild to moderate developmental retardation and leukodystrophy, which was detected on brain MRI.
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