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DBT
dihydrolipoamide branched chain transacylase E2
The DBT gene provides instructions for a crucial component of an enzyme complex responsible for breaking down specific branched-chain amino acids, such as leucine, isoleucine, and valine. The DBT gene is essential for proper metabolism, encoding part of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex.
DBT is located on the short (p) arm of chromosome 1, at band 1p21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The DBT gene, also known as dihydrolipoamide branched chain transacylase E2, is integral to the human metabolic system. It provides instructions for making a subunit of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex [PMID:17967919]. This complex is critical for breaking down specific amino acids in the body.
Pathogenic variants in the DBT gene may disrupt this metabolic process, leading to the accumulation of certain amino acids and their by-products, which can have significant health implications.
What the gene does
The protein produced by the DBT gene is known as the E2 component within the BCKD enzyme complex. This complex is located in the mitochondria, which are the energy-producing organelles within cells. The primary function of the BCKD enzyme complex is to catalyse a key step in the breakdown of the branched-chain amino acids: leucine, isoleucine, and valine [PMID:17967919].
These amino acids are obtained through the diet, particularly from protein-rich foods such as meat, dairy, and eggs. The E2 component is essential for the overall activity of the BCKD complex, ensuring that these amino acids are properly metabolised into molecules that cells can use for energy. Impaired function of the DBT-encoded protein therefore hinders the body's ability to process these vital nutrients.
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Chromosome location
The DBT gene is located on chromosome 1, specifically at position 1p21.2. This chromosomal band refers to the short (p) arm of chromosome 1, in region 2, band 1, sub-band 2. The precise genomic location helps in understanding its genetic context and how variations within this region might impact its function.
Protein structure
The DBT gene codes for a protein that is 482 amino acids in length. Its structure includes several key domains essential for its function within the branched-chain alpha-keto acid dehydrogenase complex. A Lipoyl-binding domain is found between amino acids 64 and 139. A critical region for association with the PPM1K protein is located between amino acids 145 and 160. There is also a Disordered region spanning amino acids 147-168. Furthermore, a Peripheral subunit-binding (PSBD) domain is present from amino acids 172 to 209, which is important for the assembly and function of the enzyme complex.
Key variants
Genetic variations within the DBT gene can lead to altered protein function, which may impact the metabolism of branched-chain amino acids. These variations include changes in single DNA building blocks or larger deletions or insertions. Over 70 distinct mutations within the DBT gene have been identified in individuals with maple syrup urine disease [PMID:17967919]. These pathogenic variants often disrupt the assembly or activity of the BCKD enzyme complex, leading to impaired metabolic pathways.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.113_114del | p.Cys38fs | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease |
c.1281+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease type 2 |
c.1385G>C | p.Arg462Pro | Pathogenic | ★★☆☆ | Maple syrup urine disease type 2 |
c.280C>T | p.Gln94Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease type 2 |
c.30G>A | p.Trp10Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease |
c.364dup | p.Tyr122fs | Pathogenic | ★★☆☆ | Maple syrup urine disease |
c.457del | p.Thr153fs | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease |
c.505C>T | p.Arg169Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease type 1A |
c.713del | p.Pro238fs | Pathogenic | ★★☆☆ | Maple syrup urine disease type 2 |
c.828del | p.Phe276fs | Pathogenic/Likely pathogenic | ★★☆☆ | Maple syrup urine disease |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the DBT gene are primarily associated with Maple syrup urine disease. This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected. More than 70 mutations in the DBT gene have been identified in people with maple syrup urine disease, most often in individuals with milder forms of the disorder. These milder forms can become apparent later in infancy or childhood, and without appropriate management, they may lead to developmental delays and other health problems.
Inheritance pattern
Conditions caused by pathogenic DBT variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The DBT gene is included in several UK NHS national genomic testing panels, indicating its recognised clinical significance. It is listed as 'green' in DDG2P, Early onset or syndromic epilepsy, Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders panels, signifying that variants in this gene are considered to have a strong evidence base for pathogenicity in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the DBT gene?
The DBT gene provides instructions for making a part of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. This complex is crucial for breaking down the amino acids leucine, isoleucine, and valine, which are obtained from the diet.
Which condition is associated with variants in the DBT gene?
Variants in the DBT gene are associated with Maple syrup urine disease. This condition affects the body's ability to properly metabolise certain amino acids.
How is Maple syrup urine disease inherited?
Maple syrup urine disease is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic DBT gene variant, one from each parent, to develop the condition.
References
- Quental S, Macedo-Ribeiro S, Matos R. Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community. Molecular genetics and metabolism. 2008. PMID: 18378174
- Flaschker N, Feyen O, Fend S. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. Journal of inherited metabolic disease. 2007. PMID: 17922217
- Rodríguez-Pombo P, Navarrete R, Merinero B. Mutational spectrum of maple syrup urine disease in Spain. Human mutation. 2006. PMID: 16786533
- Chi CS, Tsai CR, Chen LH. Maple syrup urine disease in the Austronesian aboriginal tribe Paiwan of Taiwan: a novel DBT (E2) gene 4.7 kb founder deletion caused by a nonhomologous recombination between LINE-1 and Alu and the carrier-frequency determination. European journal of human genetics : EJHG. 2003. PMID: 14508502
- Henneke M, Flaschker N, Helbling C. Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Human mutation. 2003. PMID: 14517957
- Nellis MM, Danner DJ. Gene preference in maple syrup urine disease. American journal of human genetics. 2001. PMID: 11112664
- Adam MP, Bick S, Mirzaa GM. Maple Syrup Urine Disease. 1993. PMID: 20301495