DBT

Summary

DBT (dihydrolipoamide branched chain transacylase E2, HGNC:2698) is a protein-coding gene on chromosome 1p21.2, encoding Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial (P11182). The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2).

The branched-chain alpha-keto acid dehydrogenase complex (BCKD) is an inner-mitochondrial enzyme complex involved in the breakdown of the branched-chain amino acids isoleucine, leucine, and valine. The BCKD complex is thought to be composed of a core of 24 transacylase (E2) subunits, and associated decarboxylase (E1), dehydrogenase (E3), and regulatory subunits. This gene encodes the transacylase (E2) subunit. Mutations in this gene result in maple syrup urine disease, type 2. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 1629 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maple syrup urine disease (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 863 total — 80 pathogenic, 76 likely-pathogenic
• Phenotypes (HPO): 6
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001918

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2698
Approved symbol	DBT
Name	dihydrolipoamide branched chain transacylase E2
Location	1p21.2
Locus type	gene with protein product
Status	Approved
Aliases	BCOADC-E2, BCKAD-E2, BCKDH-E2
Ensembl gene	ENSG00000137992
Ensembl biotype	protein_coding
OMIM	248610
Entrez	1629

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000370131, ENST00000370132, ENST00000681617, ENST00000681780, ENST00000875462, ENST00000875463, ENST00000875464, ENST00000875465, ENST00000948414

RefSeq mRNA: 3 — MANE Select: NM_001918 NM_001399969, NM_001399972, NM_001918

CCDS: CCDS767, CCDS91012

Canonical transcript exons

ENST00000370132 — 11 exons

Exon	Start	End
ENSE00000831291	100206230	100206301
ENSE00000831292	100206445	100206636
ENSE00000831293	100210694	100210771
ENSE00000831294	100214817	100214983
ENSE00000831295	100215983	100216199
ENSE00000831296	100218626	100218747
ENSE00000831297	100230733	100230914
ENSE00000831298	100235436	100235511
ENSE00000831299	100240761	100240884
ENSE00001451903	100249770	100249834
ENSE00001451905	100186919	100196422

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9708 / max 199.4382, expressed in 1680 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13513	7.6674	1671
13514	0.3035	143

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.51	gold quality
renal medulla	UBERON:0000362	99.51	gold quality
endothelial cell	CL:0000115	99.42	gold quality
cardia of stomach	UBERON:0001162	99.40	gold quality
ventral tegmental area	UBERON:0002691	99.24	gold quality
nipple	UBERON:0002030	99.23	gold quality
pylorus	UBERON:0001166	99.22	gold quality
trigeminal ganglion	UBERON:0001675	99.17	gold quality
lateral globus pallidus	UBERON:0002476	99.15	gold quality
inferior vagus X ganglion	UBERON:0005363	99.09	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.08	gold quality
subthalamic nucleus	UBERON:0001906	99.07	gold quality
visceral pleura	UBERON:0002401	99.05	gold quality
superior surface of tongue	UBERON:0007371	99.03	gold quality
superior vestibular nucleus	UBERON:0007227	99.00	gold quality
substantia nigra pars compacta	UBERON:0001965	98.98	gold quality
medulla oblongata	UBERON:0001896	98.88	gold quality
cervix squamous epithelium	UBERON:0006922	98.86	gold quality
pleura	UBERON:0000977	98.82	gold quality
pericardium	UBERON:0002407	98.74	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.73	gold quality
parietal pleura	UBERON:0002400	98.70	gold quality
cranial nerve II	UBERON:0000941	98.66	gold quality
olfactory bulb	UBERON:0002264	98.62	gold quality
penis	UBERON:0000989	98.59	gold quality
periodontal ligament	UBERON:0008266	98.57	gold quality
mucosa of urinary bladder	UBERON:0001259	98.55	gold quality
pharyngeal mucosa	UBERON:0000355	98.51	gold quality
urethra	UBERON:0000057	98.48	gold quality
saphenous vein	UBERON:0007318	98.32	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

317 targeting DBT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• two novel type IB MSUD mutations in Israeli patients, which affect the E1beta subunit in the decarboxylase (E1) component of the branched-chain alpha-ketoacid dehydrogenase complex (PMID:11448970)
• Mutation in DBT causes a subset of maple syrup urine disease in Ashkenazi Jewish population. (PMID:11509994)
• a distinct subset of antimitochondrial antibodies recognize sequences on branched-chain acyltransferase which located outside of the lipoyl binding domain, in primary biliary cirrhosis and overlap syndrome with autoimmune hepatitis (PMID:14768949)
• presence of the interdomain linker restricts the motional freedom of the hbSBD more significantly than hbLBD, and that the linker region likely exists as a soft rod rather than a flexible string in solution. (PMID:16861235)
• in our cohort more severe enzyme & clinical phenotypes of variant maple syrup urine disease were mainly associated with specific genotypes in BCKDHA gene; milder enzyme & clinical phenotypes were associated with specific genotypes in BCKDHB & DBT genes (PMID:17922217)
• 30 Maple syrup urine disease Portuguese patients studied; 17 putative mutations have been identified (6 in BCKDHA, 5 in BCKDHB and 6 in DBT); 7 of are described for the first time. (PMID:18378174)
• Examination of the deletion mutation in the E2 (DBT) gene facilitated early MSUD diagnosis and was beneficial for the determination of the proper course of treatment. (PMID:18533943)
• In 37% (12 patients) of a total of 64 alleles, the supposed maple syrup urine disease-causing mutations in Turkish patients were located in the BCKDHA gene, in 44% (14 patients) in the BCKDHB gene and in 19% (6 patients) in the DBT gene. (PMID:19480318)
• 4 novel mutations in DBT gene resulting in intermittent maple syrup urine disease in 7 Norwegian patients; pathogenic effect of the mutations is depletion of cellular protein; intermittent form of MSUD appears to be due to residual R301C mutant protein (PMID:20570198)
• Deletion in DBT gene is associated with maple syrup urine disease. (PMID:23313820)
• The novel DBT mutation c.650-651insT was more prevalent than the deleted 4.7-kb heterozygote in the Amis population. The reported 4.7-kb deletion indicating a possible founder mutation may be preserved. (PMID:24268812)
• Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease. (PMID:34883003)
• Pathogenic Homozygous Mutations in the DBT Gene (c.1174A>C) Result in Maple Syrup Urine Disease in a rs12021720 Carrier. (PMID:35657820)
• Overexpression of DBT suppresses the aggressiveness of renal clear cell carcinoma and correlates with immune infiltration. (PMID:37383233)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dbt	ENSDARG00000101561
mus_musculus	Dbt	ENSMUSG00000000340
rattus_norvegicus	Dbt	ENSRNOG00000015029
drosophila_melanogaster	Dbct	FBGN0030612
caenorhabditis_elegans		WBGENE00014054

Paralogs (3): PDHX (ENSG00000110435), DLST (ENSG00000119689), DLAT (ENSG00000150768)

Protein

Protein identifiers

Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial — P11182 (reviewed: P11182)

Alternative names: 52 kDa mitochondrial autoantigen of primary biliary cirrhosis, Branched chain 2-oxo-acid dehydrogenase complex component E2, Branched-chain alpha-keto acid dehydrogenase complex component E2, Dihydrolipoamide acetyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, Dihydrolipoamide branched chain transacylase, Dihydrolipoyllysine-residue (2-methylpropanoyl)transferase

All UniProt accessions (4): P11182, A0A7P0T9W1, A0A7P0Z494, Q5VVL7

UniProt curated annotations — full annotation on UniProt →

Function. The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acyl groups that are generated by the branched-chain alpha-keto acid decarboxylase component.

Subunit / interactions. Forms a 24-polypeptide structural core with octahedral symmetry that represents the E2 component of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. The BCKDH complex is composed of three major building blocks E1, E2 and E3. It is organized around E2, a 24-meric cubic core composed of DBT, to which are associated 6 to 12 copies of E1, and approximately 6 copies of the dehydrogenase E3, a DLD dimer. Interacts with PPM1K with a 24:1 stoichiometry; the N-terminal region (residues 49-61) of PPM1K and C-terminal linker of the lipoyl domain of DBT/E2 (residues 145-160) are critical for this interaction whereas the lipoyl prosthetic group is dispensable. This interaction requires colocalization in mitochondria. PPM1K competes with BCKDK for binding to DBT; this interaction is modulated by branched-chain alpha-keto acids (BCKAs). At steady state, BCKDH holoenzyme preferentially binds BCKDK and BCKDHA is phosphorylated. In response to high levels of BCKAs, BCKDK is replaced by PPM1K leading to BCKDHA dephosphorylation.

Subcellular location. Mitochondrion matrix.

Disease relevance. Patients with primary biliary cirrhosis (PBC) show autoantibodies against the E2 component of branched-chain alpha-keto acid dehydrogenase complex. PBC is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Maple syrup urine disease 2 (MSUD2) [MIM:620699] A form of maple syrup urine disease, an autosomal recessive metabolic disorder due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration. Clinical features include mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine. If untreated, maple syrup urine disease can lead to seizures, coma, and death. The disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still involve developmental delay and other medical problems if not treated. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 lipoyl cofactor covalently.

Similarity. Belongs to the 2-oxoacid dehydrogenase family.

RefSeq proteins (3): NP_001386898, NP_001386901, NP_001909* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR001078	2-oxoacid_DH_actylTfrase	Domain
IPR003016	2-oxoA_DH_lipoyl-BS	Binding_site
IPR004167	PSBD	Domain
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR023213	CAT-like_dom_sf	Homologous_superfamily
IPR036625	E3-bd_dom_sf	Homologous_superfamily
IPR050743	2-oxoacid_DH_E2_comp	Family

Pfam: PF00198, PF00364, PF02817

Enzyme classification (BRENDA):

• EC 2.3.1.168 — dihydrolipoyllysine-residue (2-methylpropanoyl)transferase (BRENDA: 21 organisms, 31 substrates, 6 inhibitors, 6 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6,8-BIS(SULFANYL)OCTANAMIDE	2	1
ACETYL-COA	0.11	1
ISOBUTYRYL-COA	0.1	1
ISOVALERYL-COA	0.05	1

Catalyzed reactions (Rhea), 3 shown:

• N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + 2-methylpropanoyl-CoA = N(6)-[(R)-S(8)-2-methylpropanoyldihydrolipoyl]-L-lysyl-[protein] + CoA (RHEA:18865)
• N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + 3-methylbutanoyl-CoA = N(6)-[(R)-S(8)-3-methylbutanoyldihydrolipoyl]-L-lysyl-[protein] + CoA (RHEA:84647)
• (2S)-2-methylbutanoyl-CoA + N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] = N(6)-{(R)-S(8)-[(2S)-2-methylbutanoyl]dihydrolipoyl}-L-lysyl-[protein] + CoA (RHEA:84651)

UniProt features (57 total): modified residue 16, binding site 9, strand 8, mutagenesis site 6, helix 4, sequence variant 3, domain 2, region of interest 2, sequence conflict 2, active site 2, transit peptide 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3RNM	X-RAY DIFFRACTION	2.4
1K8M	SOLUTION NMR
1K8O	SOLUTION NMR
1ZWV	SOLUTION NMR
2COO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11182-F1	78.71	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 452; 456

Ligand- & substrate-binding residues (9): 306; 349; 378; 399; 400; 403; 424; 426; 291

Post-translational modifications (16): 105, 133, 196, 196, 202, 220, 243, 250, 261, 289, 289, 295, 304, 435, 440, 440

Mutagenesis-validated functional residues (6):

Position	Phenotype
105	abolishes lipoylation but retains normal interaction with ppm1k.
147	has no effect on the interaction with ppm1k.
148	completely abolishes the interaction with ppm1k.
149	completely abolishes the interaction with ppm1k.
152	has no effect on the interaction with ppm1k.
159	has no effect on the interaction with ppm1k.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9857492	Protein lipoylation
R-HSA-9859138	BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV
R-HSA-9865113	Loss-of-function mutations in DBT cause MSUD2
R-HSA-9865125	Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD
R-HSA-9907570	Loss-of-function mutations in DLD cause MSUD3/DLDD
R-HSA-9912481	Branched-chain ketoacid dehydrogenase kinase deficiency
R-HSA-9912529	H139Hfs13* PPM1K causes a mild variant of MSUD

MSigDB gene sets: 228 (showing top): MORF_ITGA2, TGGTGCT_MIR29A_MIR29B_MIR29C, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_RAD51L3, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (2): branched-chain amino acid catabolic process (GO:0009083), branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA (GO:0120552)

GO Molecular Function (6): acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), ubiquitin protein ligase binding (GO:0031625), dihydrolipoamide branched chain acyltransferase activity (GO:0043754), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), mitochondrial nucleoid (GO:0042645), branched-chain alpha-ketoacid dehydrogenase complex (GO:0160157)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Maple Syrup Urine Disease	4
Metabolism of amino acids and derivatives	1
RHO GTPase cycle	1
Metabolism of proteins	1
Post-translational protein modification	1
Branched-chain amino acid catabolism	1
Diseases of branched-chain amino acid catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
mitochondrion	2
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
branched-chain amino acid catabolic process	1
carboxylic acid metabolic process	1
fatty-acyl-CoA metabolic process	1
acyltransferase activity	1
ubiquitin-like protein ligase binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
binding	1
catalytic activity	1
transferase activity	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
cellular anatomical structure	1
cytoskeleton	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
alpha-ketoacid dehydrogenase complex	1
transferase complex	1

Protein interactions and networks

STRING

2924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DBT	BCKDHA	P12694	890
DBT	DLD	P09622	861
DBT	BCKDHB	P21953	821
DBT	TCF3	P15883	806
DBT	CSNK1E	P49674	760
DBT	CLOCK	O15516	655
DBT	CSNK1D	P48730	619
DBT	BCAT2	O15382	585
DBT	LRRC39	Q96DD0	578
DBT	PER2	O15055	567
DBT	IVD	P26440	567
DBT	RTCA	O00442	557
DBT	CHKA	P35790	555
DBT	BMAL1	O00327	553
DBT	NUP210	Q8TEM1	544

IntAct

207 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
PPM1K	DBT	psi-mi:“MI:0914”(association)	0.790
IFIT2	IFIT3	psi-mi:“MI:0914”(association)	0.780
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
GRPEL2	DBT	psi-mi:“MI:0914”(association)	0.710
GRPEL2	DBT	psi-mi:“MI:0915”(physical association)	0.710
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670
PTGR3	DBT	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
KGD4	DLD	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
MRRF	DBT	psi-mi:“MI:0914”(association)	0.620
MMAB	DBT	psi-mi:“MI:0915”(physical association)	0.620
MRRF	DBT	psi-mi:“MI:0915”(physical association)	0.620
MMAB	DBT	psi-mi:“MI:0914”(association)	0.620
COX4I1	DBT	psi-mi:“MI:0914”(association)	0.560
CA5B	DBT	psi-mi:“MI:0915”(physical association)	0.560
CA5B	DBT	psi-mi:“MI:0914”(association)	0.560

BioGRID (262): DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Affinity Capture-MS), DBT (Co-fractionation), DBT (Affinity Capture-MS), DBT (Proximity Label-MS)

ESM2 similar proteins: A0A0D2Y5A7, G0S4X6, O00330, O59816, O94681, P08461, P0AFG6, P0AFG7, P10515, P10802, P11179, P11180, P11181, P11182, P11961, P12695, P19262, P20285, P20708, P22439, P35489, P36413, P36957, P45118, P51660, P53395, P65634, P75392, P86197, P97852, P9WIS6, P9WIS7, Q01205, Q0WQF7, Q19749, Q23571, Q59638, Q5M729, Q5ZM98, Q6FYD4

Diamond homologs: O06159, O94681, P06959, P08461, P0AFG6, P0AFG7, P10515, P10802, P11179, P11180, P11181, P11182, P16263, P19262, P20708, P27747, P31051, P36413, P36957, P37942, P45118, P45302, P52993, P57302, P57389, P65634, P86197, P86219, P9WIS6, P9WIS7, Q01205, Q1RHI5, Q23571, Q2FH26, Q2FYM2, Q2YY06, Q49XM4, Q4L6C3, Q4UKI7, Q4ULG1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 217 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Branched-chain amino acid catabolism	6	17.8×	3e-04
Mitochondrial Fatty Acid Beta-Oxidation	7	16.6×	1e-04
Citric acid cycle (TCA cycle)	5	13.2×	3e-03
Anchoring of the basal body to the plasma membrane	10	7.1×	3e-04
Loss of Nlp from mitotic centrosomes	7	6.9×	3e-03
Loss of proteins required for interphase microtubule organization from the centrosome	7	6.9×	3e-03
Mitochondrial translation	8	6.9×	3e-03
AURKA Activation by TPX2	7	6.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
branched-chain amino acid catabolic process	5	27.0×	7e-04
fatty acid beta-oxidation	6	11.5×	4e-03
mitochondrial electron transport, NADH to ubiquinone	6	11.0×	4e-03
mitochondrion organization	9	7.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

863 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	80
Likely pathogenic	76
Uncertain significance	222
Likely benign	336
Benign	70

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069743	NM_001918.5(DBT):c.365_366del (p.Tyr122fs)	Pathogenic
1072213	NM_001918.5(DBT):c.910_919del (p.Lys304fs)	Pathogenic
1076295	NM_001918.5(DBT):c.1281+2T>A	Pathogenic
11942	NM_001918.3:c.48_171del	Pathogenic
11944	NM_001918.3(DBT):c.434_435insAATACCTTGTTACCAGA	Pathogenic
11945	NM_001918.5(DBT):c.1017+1del	Pathogenic
11947	NM_001918.5(DBT):c.1448G>T (p.Ter483Leu)	Pathogenic
11948	NM_001918.5(DBT):c.294C>G (p.Ile98Met)	Pathogenic
11950	NM_001918.5(DBT):c.75_76del (p.Cys26fs)	Pathogenic
11951	NM_001918.3(DBT):c.1282-4142_*(434_435)del	Pathogenic
11952	NM_001918.5(DBT):c.1355A>G (p.His452Arg)	Pathogenic
11953	NM_001918.5(DBT):c.581C>G (p.Ser194Ter)	Pathogenic
1322190	NM_001918.5(DBT):c.52-1G>C	Pathogenic
1331436	NM_001918.5(DBT):c.363_364del (p.Tyr122fs)	Pathogenic
1342860	NM_001918.5(DBT):c.916T>C (p.Ser306Pro)	Pathogenic
1369372	NM_001918.5(DBT):c.1324C>T (p.Gln442Ter)	Pathogenic
1376132	NM_001918.5(DBT):c.1333_1336del (p.Met444_Asn445insTer)	Pathogenic
1394661	NM_001918.5(DBT):c.241_242del (p.Thr80_Val81insTer)	Pathogenic
1407245	NM_001918.5(DBT):c.1385G>C (p.Arg462Pro)	Pathogenic
1434529	NM_001918.5(DBT):c.17dup (p.Met6fs)	Pathogenic
1451318	NM_001918.5(DBT):c.961_962del (p.Gln321fs)	Pathogenic
1452071	NM_001918.5(DBT):c.516_522del (p.Ala173fs)	Pathogenic
1452719	NM_001918.5(DBT):c.531_537del (p.Arg178fs)	Pathogenic
1453507	NM_001918.5(DBT):c.1232C>T (p.Pro411Leu)	Pathogenic
1455526	NM_001918.5(DBT):c.762del (p.Glu254fs)	Pathogenic
1458060	NM_001918.5(DBT):c.304C>T (p.Gln102Ter)	Pathogenic
1458115	NM_001918.5(DBT):c.1195del (p.Ser399fs)	Pathogenic
1705103	NC_000001.10:g.(?100652477)(100661979_100671785)del	Pathogenic
195157	NM_001918.5(DBT):c.126T>G (p.Tyr42Ter)	Pathogenic
197203	NM_001918.5(DBT):c.433+1G>T	Pathogenic

SpliceAI

1946 predictions. Top by Δscore:

Variant	Effect	Δscore
1:100206443:A:AC	donor_gain	1.0000
1:100206444:C:CC	donor_gain	1.0000
1:100206444:CTGAT:C	donor_gain	1.0000
1:100210679:CT:C	donor_gain	1.0000
1:100214811:TCTCA:T	donor_loss	1.0000
1:100214812:CTCA:C	donor_loss	1.0000
1:100214813:TCA:T	donor_loss	1.0000
1:100214814:CACCT:C	donor_loss	1.0000
1:100214816:C:G	donor_loss	1.0000
1:100214980:AAGC:A	acceptor_gain	1.0000
1:100214981:AGC:A	acceptor_gain	1.0000
1:100214982:GC:G	acceptor_gain	1.0000
1:100214983:CC:C	acceptor_gain	1.0000
1:100214984:C:CC	acceptor_gain	1.0000
1:100214984:CTGA:C	acceptor_loss	1.0000
1:100214985:T:G	acceptor_loss	1.0000
1:100215977:CATTA:C	donor_loss	1.0000
1:100215978:ATTAC:A	donor_loss	1.0000
1:100215979:TTA:T	donor_loss	1.0000
1:100215980:TACCT:T	donor_loss	1.0000
1:100215982:C:CA	donor_loss	1.0000
1:100218621:CTTA:C	donor_loss	1.0000
1:100218622:TTACA:T	donor_loss	1.0000
1:100218623:TAC:T	donor_loss	1.0000
1:100218624:A:AC	donor_gain	1.0000
1:100218624:A:T	donor_loss	1.0000
1:100218625:C:CA	donor_gain	1.0000
1:100218625:CA:C	donor_gain	1.0000
1:100218625:CAT:C	donor_gain	1.0000
1:100218625:CATT:C	donor_gain	1.0000

AlphaMissense

3161 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:100230830:A:C	S112R	1.000
1:100230830:A:T	S112R	1.000
1:100230832:T:G	S112R	1.000
1:100230851:T:A	K105N	1.000
1:100230851:T:G	K105N	1.000
1:100230857:A:C	S103R	1.000
1:100230857:A:T	S103R	1.000
1:100230859:T:G	S103R	1.000
1:100230869:A:C	C99W	1.000
1:100235437:A:G	W84R	1.000
1:100235437:A:T	W84R	1.000
1:100196362:A:G	W448R	0.999
1:100196362:A:T	W448R	0.999
1:100218648:C:G	R178P	0.999
1:100218651:A:T	V177D	0.999
1:100230819:C:T	G116E	0.999
1:100230837:A:C	I110S	0.999
1:100230837:A:T	I110N	0.999
1:100230852:T:A	K105I	0.999
1:100230853:T:G	K105Q	0.999
1:100230864:A:T	V101D	0.999
1:100230870:C:T	C99Y	0.999
1:100230871:A:G	C99R	0.999
1:100230873:A:T	I98N	0.999
1:100230881:A:C	F95L	0.999
1:100230881:A:T	F95L	0.999
1:100230883:A:G	F95L	0.999
1:100235445:A:T	V81D	0.999
1:100235464:C:A	G75W	0.999
1:100235464:C:G	G75R	0.999

dbSNP variants (sampled 300 via entrez): RS1000071538 (1:100248720 G>C), RS1000169229 (1:100189392 A>C), RS1000169504 (1:100220527 C>G), RS1000201560 (1:100189015 A>G,T), RS1000275402 (1:100228457 G>A), RS1000354098 (1:100245486 A>G), RS1000359779 (1:100205741 T>C,G), RS1000393094 (1:100213530 G>A,T), RS1000448663 (1:100213362 G>A,C), RS1000455084 (1:100219247 G>A), RS1000509429 (1:100191243 G>A,C), RS1000537958 (1:100249036 G>A), RS1000547780 (1:100210064 C>A), RS1000621270 (1:100220189 A>C,G), RS1000692136 (1:100247123 G>T)

Disease associations

OMIM: gene MIM:248610 | disease phenotypes: MIM:248600, MIM:620699

GenCC curated gene-disease

Disease	Classification	Inheritance
maple syrup urine disease type 2	Definitive	Autosomal recessive
maple syrup urine disease	Strong	Autosomal recessive
maple syrup urine disease type 1A	Strong	Autosomal recessive
classic maple syrup urine disease	Supportive	Autosomal recessive
intermediate maple syrup urine disease	Supportive	Autosomal recessive
intermittent maple syrup urine disease	Supportive	Autosomal recessive
thiamine-responsive maple syrup urine disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
maple syrup urine disease	Definitive	AR

Mondo (7): maple syrup urine disease (MONDO:0009563), maple syrup urine disease type 2 (MONDO:0023693), maple syrup urine disease type 1A (MONDO:0023691), classic maple syrup urine disease (MONDO:0017051), intermediate maple syrup urine disease (MONDO:0017052), intermittent maple syrup urine disease (MONDO:0017053), thiamine-responsive maple syrup urine disease (MONDO:0017054)

Orphanet (1): Maple syrup urine disease (Orphanet:511)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001254	Lethargy
HP:0001993	Ketoacidosis
HP:0002179	Opisthotonus
HP:0003623	Neonatal onset
HP:0011463	Childhood onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004749_52	Lung cancer in ever smokers	1.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008375	Maple Syrup Urine Disease	C10.228.140.163.100.520; C16.320.565.100.608; C16.320.565.189.520; C18.452.132.100.520; C18.452.648.100.608; C18.452.648.189.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression	2
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
2-butenal	decreases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
manganese chloride	increases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
coumarin	decreases phosphorylation	1
hydroquinone	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1

Cellosaurus cell lines

5 cell lines: 2 finite cell line, 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AD58	GM00612	Finite cell line	Female
CVCL_D871	GM01364	Finite cell line	Female
CVCL_D872	GM01366	Transformed cell line	Female
CVCL_SK42	HAP1 DBT (-) 1	Cancer cell line	Male
CVCL_SK43	HAP1 DBT (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01529060	PHASE2/PHASE3	COMPLETED	Phenylbutyrate Therapy for Maple Syrup Urine Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04248062	Not specified	COMPLETED	Patient and Observer Reported Outcome Measurements in Inborn Errors of Metabolism
NCT04602325	Not specified	RECRUITING	Systemic Biomarkers of Brain Injury From Hyperammonemia
NCT04828863	Not specified	COMPLETED	Neurocognitive Outcomes and Quality of Life in Adults With Maple Syrup Urine Disease (MSUD)
NCT05051657	Not specified	COMPLETED	Evaluation of the Express Plus Range
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT06581991	Not specified	NOT_YET_RECRUITING	Liquid Valine and Isoleucine in Maple Syrup Urine Disease
NCT06664840	Not specified	NOT_YET_RECRUITING	MyRareDiet A Novel Diet Tracking Tool