BCKDHB

Summary

BCKDHB (branched chain keto acid dehydrogenase E1 subunit beta, HGNC:987) is a protein-coding gene on chromosome 6q14.1, encoding 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (P21953). Together with BCKDHA forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex.

This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants.

Source: NCBI Gene 594 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maple syrup urine disease type 1B (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 46
• Clinical variants (ClinVar): 894 total — 95 pathogenic, 99 likely-pathogenic
• Phenotypes (HPO): 10
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_183050

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:987
Approved symbol	BCKDHB
Name	branched chain keto acid dehydrogenase E1 subunit beta
Location	6q14.1
Locus type	gene with protein product
Status	Approved
Aliases	OVD1B
Ensembl gene	ENSG00000083123
Ensembl biotype	protein_coding
OMIM	248611
Entrez	594

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000320393, ENST00000356489, ENST00000369760, ENST00000468520, ENST00000486968, ENST00000491328, ENST00000879176, ENST00000879177, ENST00000929318, ENST00000929319

RefSeq mRNA: 14 — MANE Select: NM_183050 NM_000056, NM_001318975, NM_001424035, NM_001424036, NM_001424037, NM_001424038, NM_001424039, NM_001424040, NM_001424041, NM_001424042, NM_001424043, NM_001424044, NM_001424045, NM_183050

CCDS: CCDS4994

Canonical transcript exons

ENST00000320393 — 10 exons

Exon	Start	End
ENSE00000798033	80167678	80167811
ENSE00000798034	80168875	80169030
ENSE00003497825	80273135	80273221
ENSE00003527706	80129161	80129229
ENSE00003541425	80171282	80171390
ENSE00003630536	80200934	80201031
ENSE00003643846	80127547	80127624
ENSE00003669325	80203102	80203212
ENSE00003677486	80343664	80346270
ENSE00003845936	80106671	80106889

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 93.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1921 / max 155.8396, expressed in 1777 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68704	12.9363	1764
68703	3.2557	1466

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	93.24	gold quality
rectum	UBERON:0001052	89.28	gold quality
liver	UBERON:0002107	88.88	gold quality
mucosa of transverse colon	UBERON:0004991	88.20	gold quality
calcaneal tendon	UBERON:0003701	86.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.06	gold quality
transverse colon	UBERON:0001157	85.85	gold quality
ventricular zone	UBERON:0003053	85.64	gold quality
popliteal artery	UBERON:0002250	85.43	gold quality
tibial artery	UBERON:0007610	85.43	gold quality
body of stomach	UBERON:0001161	85.20	gold quality
heart left ventricle	UBERON:0002084	85.03	gold quality
mucosa of stomach	UBERON:0001199	84.96	gold quality
cardiac ventricle	UBERON:0002082	84.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.48	gold quality
saliva-secreting gland	UBERON:0001044	84.36	gold quality
colonic epithelium	UBERON:0000397	84.31	gold quality
minor salivary gland	UBERON:0001830	84.29	gold quality
right ovary	UBERON:0002118	84.20	gold quality
aorta	UBERON:0000947	84.16	gold quality
stomach	UBERON:0000945	84.05	gold quality
tibial nerve	UBERON:0001323	83.98	gold quality
left ovary	UBERON:0002119	83.91	gold quality
body of pancreas	UBERON:0001150	83.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.62	gold quality
parotid gland	UBERON:0001831	83.61	gold quality
left coronary artery	UBERON:0001626	83.16	gold quality
heart	UBERON:0000948	83.15	gold quality
secondary oocyte	CL:0000655	82.88	gold quality
colon	UBERON:0001155	82.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting BCKDHB, 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-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-3157-5P	97.41	67.61	998

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 21)

• Founder mutation in Ashkenazi Jewish population that causes maple syrup urine disease. (PMID:11509994)
• analysis of roles of His291-alpha and His146-beta’ in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase: refined phosphorylation loop structure in the active site (PMID:12902323)
• cross-talk between thiamin diphosphate binding and phosphorylation loop conformation has an effect on human branched-chain alpha-keto acid decarboxylase/dehydrogenase (PMID:15166214)
• A key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the thiamine diphosphate cofactor through interactions with its thiazolium ring. (PMID:16472748)
• the two active sites in the E1b heterotetramer operate independently during the ThDP-dependent decarboxylation reaction (PMID:17329260)
• Reconstructed haplotype from BCKDHB variants was associated with premature ovarian failure. (PMID:17524396)
• 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)
• 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)
• BCKDHA and BCKDHB mutations might be primarily responsible for maple syrup urine disease in the Indian population. (PMID:22593002)
• Mutations in BCKDHB gene is associated with maple syrup urine disease. (PMID:23313820)
• we describe the presenting symptoms and clinical course of a Chinese boy with intermittent Intermittent maple syrup urine disease from BCKDHB gene mutation (PMID:26239723)
• Five novel mutations in BCKDHB were identified in MSUD patients. (PMID:26453840)
• we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants (PMID:26830710)
• Data suggest that the following genetic modifications are involved in patients with maple syrup urine disease in Iran: (1) mutation in BCKDHA (branched chain keto acid dehydrogenase E1 alpha); (2) mutation in BCKDHB (branched chain keto acid dehydrogenase E1 subunit beta); (3) mutation in DBT (dihydrolipoamide branched chain transacylase E2; one patient). (PMID:29306928)
• Six different novel genetic variants were validated in BCKDHB gene and BCKDHA gene, including c.523 T > C, c.659delA, c.550delT, c.863G > A and two gross deletions (PMID:29307017)
• Two heterozygous mutations c.284G>C (p.Gly95Ala) and c.853C>T (p.Arg285*) of the BCKDHB gene were associated with a pedigree affected with maple syrup urine disease. (PMID:30298494)
• Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease. (PMID:32515140)
• Neonatal maple syrup urine disease in China: two novel mutations in the BCKDHB gene and literature review. (PMID:34187135)
• Association of BCAT2 and BCKDH polymorphisms with clinical, anthropometric and biochemical parameters in young adults. (PMID:34511290)
• Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease. (PMID:34883003)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bckdhb	ENSDARG00000014676
mus_musculus	Bckdhb	ENSMUSG00000032263
rattus_norvegicus	Bckdhb	ENSRNOG00000009928
drosophila_melanogaster	BckdhB	FBGN0039993
caenorhabditis_elegans	bckd-1B	WBGENE00006518

Paralogs (4): TKTL1 (ENSG00000007350), TKTL2 (ENSG00000151005), TKT (ENSG00000163931), PDHB (ENSG00000168291)

Protein

Protein identifiers

2-oxoisovalerate dehydrogenase subunit beta, mitochondrial — P21953 (reviewed: P21953)

Alternative names: Branched-chain alpha-keto acid dehydrogenase E1 component beta chain

All UniProt accessions (2): P21953, A0A140VKB3

UniProt curated annotations — full annotation on UniProt →

Function. Together with BCKDHA forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The BCKD complex catalyzes the multi-step oxidative decarboxylation of alpha-ketoacids derived from the branched-chain amino-acids valine, leucine and isoleucine producing CO2 and acyl-CoA which is subsequently utilized to produce energy. The E1 subunit catalyzes the first step with the decarboxylation of the alpha-ketoacid forming an enzyme-product intermediate. A reductive acylation mediated by the lipoylamide cofactor of E2 extracts the acyl group from the E1 active site for the next step of the reaction.

Subunit / interactions. Heterotetramer of 2 alpha/BCKDHA and 2 beta chains/BCKDHB that forms the branched-chain alpha-keto acid decarboxylase (E1) component of the BCKD complex. The branched-chain alpha-ketoacid dehydrogenase is a large complex 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.

Subcellular location. Mitochondrion matrix.

Disease relevance. Maple syrup urine disease 1B (MSUD1B) [MIM:620698] 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.

Isoforms (2)

UniProt ID	Names	Canonical?
P21953-1	1	yes
P21953-2	2

RefSeq proteins (14): NP_000047, NP_001305904, NP_001410964, NP_001410965, NP_001410966, NP_001410967, NP_001410968, NP_001410969, NP_001410970, NP_001410971, NP_001410972, NP_001410973, NP_001410974, NP_898871* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005475	Transketolase-like_Pyr-bd	Domain
IPR009014	Transketo_C/PFOR_II	Homologous_superfamily
IPR029061	THDP-binding	Homologous_superfamily
IPR033248	Transketolase_C	Domain

Pfam: PF02779, PF02780

Catalyzed reactions (Rhea), 3 shown:

• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + 3-methyl-2-oxobutanoate + H(+) = N(6)-[(R)-S(8)-2-methylpropanoyldihydrolipoyl]-L-lysyl-[protein] + CO2 (RHEA:13457)
• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + 4-methyl-2-oxopentanoate + H(+) = N(6)-[(R)-S(8)-3-methylbutanoyldihydrolipoyl]-L-lysyl-[protein] + CO2 (RHEA:84639)
• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + (S)-3-methyl-2-oxopentanoate + H(+) = N(6)-{(R)-S(8)-[(2S)-2-methylbutanoyl]dihydrolipoyl}-L-lysyl-[protein] + CO2 (RHEA:84643)

UniProt features (60 total): helix 18, strand 15, sequence variant 7, binding site 7, turn 5, modified residue 2, splice variant 2, sequence conflict 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
2BFD	X-RAY DIFFRACTION	1.39
2BFF	X-RAY DIFFRACTION	1.46
1X7Y	X-RAY DIFFRACTION	1.57
2BFC	X-RAY DIFFRACTION	1.64
2BFE	X-RAY DIFFRACTION	1.69
1X7Z	X-RAY DIFFRACTION	1.72
1X7W	X-RAY DIFFRACTION	1.73
2BFB	X-RAY DIFFRACTION	1.77
2BEW	X-RAY DIFFRACTION	1.79
1V1R	X-RAY DIFFRACTION	1.8
2BEV	X-RAY DIFFRACTION	1.8
1U5B	X-RAY DIFFRACTION	1.83
1WCI	X-RAY DIFFRACTION	1.84
1OLS	X-RAY DIFFRACTION	1.85
2J9F	X-RAY DIFFRACTION	1.88
2BEU	X-RAY DIFFRACTION	1.89
1OLU	X-RAY DIFFRACTION	1.9
1V16	X-RAY DIFFRACTION	1.9
1V11	X-RAY DIFFRACTION	1.95
1V1M	X-RAY DIFFRACTION	2
1X80	X-RAY DIFFRACTION	2
1X7X	X-RAY DIFFRACTION	2.1
1OLX	X-RAY DIFFRACTION	2.25
1DTW	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21953-F1	90.86	0.85

Functional residue map

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

Ligand- & substrate-binding residues (7): 152; 178; 180; 181; 228; 231; 233

Post-translational modifications (2): 241, 232

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
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: 237 (showing top): MODULE_93, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, 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, GERY_CEBP_TARGETS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_14HR_DN, LANDIS_ERBB2_BREAST_PRENEOPLASTIC_DN, COATES_MACROPHAGE_M1_VS_M2_UP

GO Biological Process (4): response to nutrient (GO:0007584), branched-chain amino acid catabolic process (GO:0009083), branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA (GO:0120552), lipid metabolic process (GO:0006629)

GO Molecular Function (3): branched-chain 2-oxo acid dehydrogenase activity (GO:0003863), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nucleoplasm (GO:0005654), nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), branched-chain alpha-ketoacid dehydrogenase complex (GO:0160157)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Maple Syrup Urine Disease	4
Metabolism of amino acids and derivatives	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
nuclear lumen	2
response to nutrient levels	1
response to chemical	1
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
primary metabolic process	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor	1
binding	1
catalytic activity	1
cellular anatomical structure	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
transferase complex	1

Protein interactions and networks

STRING

2468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCKDHB	BCKDHA	P12694	999
BCKDHB	DLD	P09622	949
BCKDHB	BCAT2	O15382	909
BCKDHB	DBT	P11182	821
BCKDHB	PCCB	P05166	667
BCKDHB	PCCA	P05165	653
BCKDHB	BCKDK	O14874	643
BCKDHB	PPM1K	Q8N3J5	624
BCKDHB	BCAT1	P54687	610
BCKDHB	MCCC1	Q96RQ3	574
BCKDHB	IVD	P26440	561
BCKDHB	MCCC2	Q9HCC0	548
BCKDHB	ALDH6A1	Q02252	545
BCKDHB	ACADSB	P45954	544
BCKDHB	HIBCH	Q6NVY1	518

IntAct

64 interactions, top by confidence:

A	B	Type	Score
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
BCKDHB	BCKDHA	psi-mi:“MI:0407”(direct interaction)	0.840
BCKDHA	BCKDHB	psi-mi:“MI:0407”(direct interaction)	0.840
PPM1K	DBT	psi-mi:“MI:0914”(association)	0.790
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
POLB	PARP1	psi-mi:“MI:0914”(association)	0.530
BCKDHB	DBT	psi-mi:“MI:0914”(association)	0.530
POLB	H2AC11	psi-mi:“MI:0914”(association)	0.530
TCF25	BCKDHB	psi-mi:“MI:0914”(association)	0.530
POLL	BCKDHA	psi-mi:“MI:0914”(association)	0.510
BCKDHB		psi-mi:“MI:0915”(physical association)	0.400
DUT	BCKDHB	psi-mi:“MI:0915”(physical association)	0.400
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
HDAC6	GLOD5	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ACBD3	PDCD6	psi-mi:“MI:0914”(association)	0.350

BioGRID (84): BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), DBT (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), LARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2I2F2I5, A5A6L0, A7MB35, G0SHF3, O13366, O24457, P07342, P08559, P14874, P16387, P21839, P21953, P26267, P26268, P26284, P28838, P28839, P29803, P29804, P34385, P35486, P35487, P35738, P52899, P52900, P52901, P52902, P52903, Q06437, Q10489, Q2NL26, Q3ZC84, Q41768, Q41769, Q54C70, Q5R432, Q5R490, Q654V6, Q6K2E8, Q6P3A8

Diamond homologs: A2CI50, G0RYE0, O34591, O44451, O64688, O66113, P09061, P0A0A1, P0A0A2, P0A0A3, P11177, P11966, P21839, P21874, P21882, P21953, P26269, P27746, P32473, P35488, P35738, P37941, P47515, P49432, P51266, P52904, P75391, P99063, P9WF02, P9WIS0, P9WIS1, Q09171, Q0J0H4, Q10G39, Q1ACL0, Q1RJX3, Q1XDM1, Q2QM55, Q32RM2, Q32RS0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	95
Likely pathogenic	99
Uncertain significance	212
Likely benign	318
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069097	NM_183050.4(BCKDHB):c.196G>A (p.Gly66Arg)	Pathogenic
1070281	NC_000006.11:g.(?80816391)(81053541_?)del	Pathogenic
1072285	NM_183050.4(BCKDHB):c.234_249del (p.Ser79fs)	Pathogenic
1072640	NM_183050.4(BCKDHB):c.396del (p.Phe132fs)	Pathogenic
1076705	NM_183050.4(BCKDHB):c.322dup (p.Val108fs)	Pathogenic
11939	NM_183050.4(BCKDHB):c.356T>G (p.Val119Gly)	Pathogenic
11941	BCKDHB, 8-BP INS, NT1109	Pathogenic
1341189	GRCh37/hg19 6q13-14.1(chr6:72799054-83275894)x1	Pathogenic
1413124	NM_183050.4(BCKDHB):c.525dup (p.Asn176Ter)	Pathogenic
1418173	NM_183050.4(BCKDHB):c.25_35dup (p.Arg13fs)	Pathogenic
1430401	NM_183050.4(BCKDHB):c.272del (p.Ala91fs)	Pathogenic
1440763	NM_183050.4(BCKDHB):c.667G>T (p.Gly223Ter)	Pathogenic
1454198	NM_183050.4(BCKDHB):c.196G>C (p.Gly66Arg)	Pathogenic
1457763	NM_183050.4(BCKDHB):c.477+1G>A	Pathogenic
1459386	NC_000006.11:g.(?80816317)(80838956_?)del	Pathogenic
1459691	NC_000006.11:g.(?80816411)(80816626_?)del	Pathogenic
1487606	NM_183050.4(BCKDHB):c.641T>A (p.Ile214Lys)	Pathogenic
1997732	NM_183050.4(BCKDHB):c.722_731dup (p.Tyr244Ter)	Pathogenic
2010895	NM_183050.4(BCKDHB):c.197-2A>C	Pathogenic
2011205	NM_183050.4(BCKDHB):c.197-1G>C	Pathogenic
2018920	NM_183050.4(BCKDHB):c.29_32del (p.Trp10fs)	Pathogenic
2136445	NM_183050.4(BCKDHB):c.662_663del (p.Ala221fs)	Pathogenic
224055	NM_183050.4(BCKDHB):c.554C>T (p.Pro185Leu)	Pathogenic
224056	NM_183050.4(BCKDHB):c.197-2A>G	Pathogenic
224057	NM_183050.4(BCKDHB):c.3G>A (p.Met1Ile)	Pathogenic
224058	NM_001318975.1(BCKDHB):c.-70_-15+207del	Pathogenic
224059	NM_183050.4(BCKDHB):c.1065del (p.Pro356fs)	Pathogenic
224060	NM_183050.4(BCKDHB):c.401T>A (p.Ile134Asn)	Pathogenic
2426770	NC_000006.11:g.(?79650410)(80912949_?)del	Pathogenic
2427612	NC_000006.11:g.(?80837244)(80982958_?)del	Pathogenic

SpliceAI

3519 predictions. Top by Δscore:

Variant	Effect	Δscore
6:80127541:TCACA:T	acceptor_loss	1.0000
6:80127542:CACA:C	acceptor_loss	1.0000
6:80127543:A:AG	acceptor_gain	1.0000
6:80127543:ACAG:A	acceptor_gain	1.0000
6:80127544:C:G	acceptor_gain	1.0000
6:80127544:CAGG:C	acceptor_loss	1.0000
6:80127545:A:AC	acceptor_loss	1.0000
6:80127545:A:AG	acceptor_gain	1.0000
6:80127545:AG:A	acceptor_gain	1.0000
6:80127546:G:GG	acceptor_gain	1.0000
6:80127546:G:T	acceptor_loss	1.0000
6:80127546:GG:G	acceptor_gain	1.0000
6:80127546:GGGC:G	acceptor_gain	1.0000
6:80127546:GGGCA:G	acceptor_gain	1.0000
6:80129155:TTTCA:T	acceptor_loss	1.0000
6:80129156:TTCA:T	acceptor_loss	1.0000
6:80129157:TCA:T	acceptor_loss	1.0000
6:80129159:A:AG	acceptor_gain	1.0000
6:80129159:AGT:A	acceptor_loss	1.0000
6:80129160:G:GA	acceptor_gain	1.0000
6:80129160:GT:G	acceptor_gain	1.0000
6:80129160:GTA:G	acceptor_gain	1.0000
6:80129160:GTAA:G	acceptor_gain	1.0000
6:80129160:GTAAT:G	acceptor_gain	1.0000
6:80129226:TATGG:T	donor_loss	1.0000
6:80129229:GGTA:G	donor_loss	1.0000
6:80129230:G:A	donor_loss	1.0000
6:80129230:G:GG	donor_gain	1.0000
6:80129231:TAAG:T	donor_loss	1.0000
6:80167670:A:AG	acceptor_gain	1.0000

AlphaMissense

2556 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:80129176:A:T	D97V	1.000
6:80129196:T:C	F104L	1.000
6:80129198:T:A	F104L	1.000
6:80129198:T:G	F104L	1.000
6:80167779:T:C	F149L	1.000
6:80167781:T:A	F149L	1.000
6:80167781:T:G	F149L	1.000
6:80167786:A:T	D151V	1.000
6:80168983:C:G	H196D	1.000
6:80129170:G:A	G95D	0.999
6:80129170:G:T	G95V	0.999
6:80129175:G:C	D97H	0.999
6:80129176:A:C	D97A	0.999
6:80129177:T:A	D97E	0.999
6:80129177:T:G	D97E	0.999
6:80129196:T:A	F104I	0.999
6:80129196:T:G	F104V	0.999
6:80129204:C:G	C106W	0.999
6:80167690:T:A	V119D	0.999
6:80167705:T:G	L124W	0.999
6:80167711:A:T	E126V	0.999
6:80167712:A:C	E126D	0.999
6:80167712:A:T	E126D	0.999
6:80167716:G:A	G128R	0.999
6:80167716:G:C	G128R	0.999
6:80167725:G:A	G131R	0.999
6:80167725:G:C	G131R	0.999
6:80167726:G:A	G131E	0.999
6:80167738:G:A	G135E	0.999
6:80167780:T:C	F149S	0.999

dbSNP variants (sampled 300 via entrez): RS1000012143 (6:80195115 A>G), RS1000017436 (6:80280883 G>T), RS1000031188 (6:80153062 A>T), RS1000034523 (6:80238958 C>A,T), RS1000039436 (6:80323139 G>A,C), RS1000047891 (6:80145967 G>A), RS1000052174 (6:80372361 G>A), RS1000061022 (6:80409156 G>T), RS1000075164 (6:80214074 A>G), RS1000080120 (6:80145717 G>A,T), RS1000091767 (6:80409401 G>C), RS1000092874 (6:80443780 A>G), RS1000125129 (6:80435222 A>G,T), RS1000130224 (6:80290061 A>G), RS1000155089 (6:80106485 A>G,T)

Disease associations

OMIM: gene MIM:248611 | disease phenotypes: MIM:248600, MIM:620698

GenCC curated gene-disease

Disease	Classification	Inheritance
maple syrup urine disease type 1B	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 type 1B	Definitive	AR

Mondo (7): maple syrup urine disease (MONDO:0009563), maple syrup urine disease type 1B (MONDO:0023692), 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

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0002179	Opisthotonus
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0010910	Hypervalinemia
HP:0010911	Hyperleucinemia
HP:0010913	Hyperisoleucinemia
HP:0011968	Feeding difficulties

GWAS associations

46 associations (top):

Study	Trait	p-value
GCST001859_33	Thiazide-induced adverse metabolic effects in hypertensive patients	7.000000e-06
GCST001956_39	Height	3.000000e-09
GCST002647_55	Height	3.000000e-26
GCST002843_40	Sitting height ratio	1.000000e-08
GCST003998_9	Joint mobility (Beighton score)	3.000000e-10
GCST004562_102	Waist circumference adjusted for body mass index	4.000000e-06
GCST004562_131	Waist circumference adjusted for body mass index	5.000000e-08
GCST004563_108	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	4.000000e-07
GCST004564_54	Waist circumference adjusted for BMI in active individuals	4.000000e-07
GCST004639_21	Prudent dietary pattern	4.000000e-06
GCST006627_86	Diastolic blood pressure	5.000000e-09
GCST008163_172	Height	1.000000e-07
GCST008163_398	Height	2.000000e-06
GCST008282_1	Spine bone size	1.000000e-16
GCST008789_8	Adolescent idiopathic scoliosis	3.000000e-09
GCST008839_205	Height	6.000000e-27
GCST008839_252	Height	2.000000e-09
GCST008839_398	Height	1.000000e-21
GCST010197_7	Protein level change in low calorie diet obesity intervention	9.000000e-06
GCST012226_481	Waist circumference adjusted for body mass index	4.000000e-12
GCST012226_483	Waist circumference adjusted for body mass index	3.000000e-09
GCST012226_484	Waist circumference adjusted for body mass index	4.000000e-08
GCST012226_486	Waist circumference adjusted for body mass index	2.000000e-12
GCST012227_21	Hip circumference adjusted for BMI	2.000000e-08
GCST012228_269	Waist-hip index	2.000000e-10
GCST012228_270	Waist-hip index	2.000000e-09
GCST012228_271	Waist-hip index	4.000000e-09
GCST012230_459	Waist-to-hip ratio adjusted for BMI	5.000000e-10
GCST012230_460	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST012230_461	Waist-to-hip ratio adjusted for BMI	2.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0007118	sitting height ratio
EFO:0007905	joint hypermobility measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0008111	diet measurement
EFO:0006336	diastolic blood pressure
EFO:0004508	spine bone size
EFO:0004747	protein measurement
EFO:0010731	response to low calorie diet
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass

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: yes

ChEMBL targets (1): CHEMBL5465287 (SINGLE PROTEIN)

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
Benzo(a)pyrene	affects methylation, decreases expression	4
Valproic Acid	affects expression, decreases methylation, increases expression	4
Aflatoxin B1	increases methylation, decreases expression, decreases methylation	3
bisphenol A	decreases expression, increases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tanshinone	decreases expression	1
benzo(e)pyrene	increases methylation	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Coumestrol	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5338432	Binding	Binding affinity to BCKDHB (unknown origin) at 200 uM preincubated for 2 hrs followed by pronase addition and measured after 30 mins by coomassie blue staining based SDS-PAGE gel analysis	Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans. — J Nat Prod

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3ZD	SDQLCHi033-A	Induced pluripotent stem cell	Female
CVCL_XJ78	SDQLCHi006-A	Induced pluripotent stem cell	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