BCKDHA

Summary

BCKDHA (branched chain keto acid dehydrogenase E1 subunit alpha, HGNC:986) is a protein-coding gene on chromosome 19q13.2, encoding 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (P12694). Together with BCKDHB forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex.

The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 593 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maple syrup urine disease type 1A (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 838 total — 65 pathogenic, 77 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_000709

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:986
Approved symbol	BCKDHA
Name	branched chain keto acid dehydrogenase E1 subunit alpha
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MSU
Ensembl gene	ENSG00000248098
Ensembl biotype	protein_coding
OMIM	608348
Entrez	593

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000269980, ENST00000457836, ENST00000535632, ENST00000538423, ENST00000541315, ENST00000542943, ENST00000544905, ENST00000545787, ENST00000906421, ENST00000906422, ENST00000906423, ENST00000906424, ENST00000906425, ENST00000906426, ENST00000906427, ENST00000919033, ENST00000919034, ENST00000967145, ENST00000967147

RefSeq mRNA: 2 — MANE Select: NM_000709 NM_000709, NM_001164783

CCDS: CCDS12581

Canonical transcript exons

ENST00000269980 — 9 exons

Exon	Start	End
ENSE00002223278	41424438	41425002
ENSE00002310464	41397818	41397935
ENSE00003578435	41422998	41423169
ENSE00003581492	41410637	41410816
ENSE00003582058	41410923	41411009
ENSE00003617150	41422164	41422370
ENSE00003622819	41419135	41419296
ENSE00003629609	41422629	41422770
ENSE00003674046	41414049	41414157

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.1295 / max 377.3534, expressed in 1824 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176027	61.1295	1824

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.84	gold quality
right adrenal gland	UBERON:0001233	97.07	gold quality
apex of heart	UBERON:0002098	96.97	gold quality
right adrenal gland cortex	UBERON:0035827	96.86	gold quality
right lobe of liver	UBERON:0001114	96.79	gold quality
left adrenal gland	UBERON:0001234	96.63	gold quality
left adrenal gland cortex	UBERON:0035825	96.47	gold quality
heart left ventricle	UBERON:0002084	96.28	gold quality
gastrocnemius	UBERON:0001388	96.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.01	gold quality
muscle of leg	UBERON:0001383	95.76	gold quality
skeletal muscle organ	UBERON:0014892	95.68	gold quality
esophagus mucosa	UBERON:0002469	95.56	gold quality
adrenal gland	UBERON:0002369	95.18	gold quality
heart	UBERON:0000948	94.40	gold quality
body of stomach	UBERON:0001161	94.20	gold quality
liver	UBERON:0002107	94.12	gold quality
right atrium auricular region	UBERON:0006631	94.10	gold quality
adult mammalian kidney	UBERON:0000082	93.98	gold quality
fundus of stomach	UBERON:0001160	93.75	gold quality
skeletal muscle tissue	UBERON:0001134	93.54	gold quality
right lobe of thyroid gland	UBERON:0001119	93.52	gold quality
left lobe of thyroid gland	UBERON:0001120	93.45	gold quality
esophagus	UBERON:0001043	93.36	gold quality
skin of leg	UBERON:0001511	93.16	gold quality
cortex of kidney	UBERON:0001225	93.12	gold quality
thyroid gland	UBERON:0002046	93.05	gold quality
zone of skin	UBERON:0000014	92.92	gold quality
metanephros cortex	UBERON:0010533	92.90	gold quality
skin of abdomen	UBERON:0001416	92.86	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.37
E-ENAD-17	no	1032.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting BCKDHA, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-496	98.66	69.80	931
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-125A-3P	97.04	66.92	902
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-1539	92.91	60.97	91

Literature-anchored findings (GeneRIF, showing 22)

• the conformational stability underlying the folding of this lipoic acid bearing domain of human mitochondrial branched chain alpha-ketoacid dehydrogenase (PMID:15322287)
• A list of nine primary candidate genes for T2D and five for obesity were identified in this paper. Two genes, LPL and BCKDHA, were common to these two sets. (PMID:16757574)
• 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)
• Case Report: Maple syrup urine disease due to a new large deletion at BCKDHA caused by non-homologous recombination. (PMID:19085071)
• A founder mutation in the BCKDHA is responsible for the high incidence of the maple syrup urine disease among Portuguese Gypsies. (PMID:19456321)
• 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)
• five mutations, three of them novel, responsible for maple syrup urine disease (PMID:19715473)
• Case Report: functional characterization of the novel intronic nucleotide change c.288+9C>T within the BCKDHA gene in maple syrup urine disease. (PMID:20431954)
• identified 4 novel mutations of the BCKDHA gene in 3 Korean newborns; to the best of knowledge, this is the first report of maple syrup urine disease confirmed by genetic analysis in Korea (PMID:21844576)
• BCKDHA and BCKDHB mutations might be primarily responsible for maple syrup urine disease in the Indian population. (PMID:22593002)
• autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome. (PMID:22956686)
• Data from infant/her heterozygous parents (first cousins) suggest homozygous mutation (S144I) in BCKDHA can result in maple syrup urine disease (IA); molecular modeling suggests this missense mutation in exon 4 affects protein stability. [CASE STUDY] (PMID:23729548)
• 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)
• Targeted parallel sequencing revealed novel mutations in the gene BCKDHA for prenatal testing of maple syrup urine disease. (PMID:24603436)
• Five novel mutations in BCKDHA 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)
• pathogenic effect of a novel variant of BCKDHA leading to classical maple syrup urine disease (PMID:29673582)
• 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	bckdha	ENSDARG00000040555
mus_musculus	Bckdha	ENSMUSG00000060376
rattus_norvegicus	Bckdha	ENSRNOG00000020607
drosophila_melanogaster	BckdhA	FBGN0037709
caenorhabditis_elegans		WBGENE00012713

Paralogs (2): PDHA1 (ENSG00000131828), PDHA2 (ENSG00000163114)

Protein

Protein identifiers

2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial — P12694 (reviewed: P12694)

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

All UniProt accessions (5): P12694, F5GXU9, H0YH20, H0YH31, Q59EI3

UniProt curated annotations — full annotation on UniProt →

Function. Together with BCKDHB 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. Interacts with PPM1K.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Phosphorylated at Ser-337 by BCKDK and dephosphorylated by protein phosphatase PPM1K.

Disease relevance. Maple syrup urine disease 1A (MSUD1A) [MIM:248600] 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.

Similarity. Belongs to the BCKDHA family.

Isoforms (2)

UniProt ID	Names	Canonical?
P12694-1	1	yes
P12694-2	2

RefSeq proteins (2): NP_000700, NP_001158255 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001017	DH_E1	Domain
IPR029061	THDP-binding	Homologous_superfamily
IPR050771	Alpha-ketoacid_DH_E1_comp	Family

Pfam: PF00676

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 (90 total): sequence variant 22, helix 20, binding site 14, strand 11, modified residue 7, turn 6, sequence conflict 3, splice variant 2, mutagenesis site 2, transit peptide 1, chain 1, region of interest 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-P12694-F1	91.82	0.88

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 (14): 238; 239; 240; 265; 267; 269; 336; 158; 159; 206; 207; 208 …

Post-translational modifications (7): 337, 338, 339, 347, 356, 356, 380

Mutagenesis-validated functional residues (2):

Position	Phenotype
337	substantially decreases the stability of the bckd complex.
347	does not affect the stability of the bckd complex.

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: 249 (showing top): MODULE_93, MODULE_45, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, MODULE_16, USF_C, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GTGCCTT_MIR506, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, MODULE_239, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, JEON_SMAD6_TARGETS_DN

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): branched-chain 2-oxo acid dehydrogenase activity (GO:0003863), carboxy-lyase activity (GO:0016831), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor (GO:0016624)

GO Cellular Component (3): 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
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
oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor	1
carbon-carbon lyase activity	1
cation binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	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

1968 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCKDHA	BCKDHB	P21953	999
BCKDHA	DLD	P09622	971
BCKDHA	BCAT2	O15382	934
BCKDHA	DBT	P11182	890
BCKDHA	BCKDK	O14874	768
BCKDHA	PPM1K	Q8N3J5	677
BCKDHA	PCCB	P05166	664
BCKDHA	BCAT1	P54687	657
BCKDHA	IVD	P26440	641
BCKDHA	PCCA	P05165	615
BCKDHA	MCCC1	Q96RQ3	578
BCKDHA	MCCC2	Q9HCC0	539
BCKDHA	ACADSB	P45954	521
BCKDHA	MMAB	Q96EY8	520
BCKDHA	HSPE1	P61604	500

IntAct

150 interactions, top by confidence:

A	B	Type	Score
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
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
NDUFAF4	NDUFS7	psi-mi:“MI:0914”(association)	0.790
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
POLB	PARP1	psi-mi:“MI:0914”(association)	0.530
BCKDHB	DBT	psi-mi:“MI:0914”(association)	0.530
COQ2	SLC25A5	psi-mi:“MI:0914”(association)	0.530

BioGRID (203): BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), BCKDHA (Affinity Capture-MS)

ESM2 similar proteins: A0A7J6EK66, A0A803PDZ0, A2ATU0, A5A6H9, D3ZQD3, F4IW47, O20250, O22567, O45924, O61199, O78328, P09060, P11178, P11960, P12694, P21881, P33315, P47516, P50136, P75390, Q02218, Q148N0, Q1QQ40, Q21F93, Q23629, Q38854, Q4KLP0, Q4MTG0, Q54M22, Q5PRA2, Q5R7H0, Q5R9L8, Q5RCB8, Q5XI78, Q60597, Q60HE2, Q623T0, Q68EW0, Q6P286, Q6P6Z8

Diamond homologs: A5A6H9, F4KIN4, O31404, O45924, O66112, P09060, P11178, P11960, P12694, P21873, P21881, P35485, P37940, P50136, P52903, P60089, P60090, P9WIS2, P9WIS3, Q1XDM0, Q4MTG0, Q54M22, Q5HGZ1, Q5HQ76, Q5SLR4, Q654V6, Q6GAC1, Q6GHZ2, Q72GU1, Q820A6, Q84JL2, Q8CPN3, Q8HXY4, Q9I1M2, Q9LPL5, Q9R9N5, O23160, P16387, P26267, P26268

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BCKDK	down-regulates	BCKDHA	phosphorylation
PPM1K	“up-regulates activity”	BCKDHA	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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
Mitochondrial protein import	8	11.5×	5e-05
Complex I biogenesis	7	9.9×	5e-04
Protein localization	6	9.8×	2e-03
Respiratory electron transport	11	8.9×	2e-05
Mitochondrial protein degradation	9	8.8×	7e-05
Aerobic respiration and respiratory electron transport	11	8.3×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	6	15.9×	1e-03
mitochondrial electron transport, NADH to ubiquinone	6	13.9×	1e-03
proton motive force-driven mitochondrial ATP synthesis	7	11.9×	1e-03
aerobic respiration	6	9.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	65
Likely pathogenic	77
Uncertain significance	175
Likely benign	358
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069052	NM_000709.4(BCKDHA):c.130C>T (p.Gln44Ter)	Pathogenic
1073900	NM_000709.4(BCKDHA):c.884C>A (p.Ser295Ter)	Pathogenic
1075126	NM_000709.4(BCKDHA):c.701_702del (p.Cys234fs)	Pathogenic
1075614	NC_000019.9:g.(?41903723)(41930736_?)del	Pathogenic
1075615	NC_000019.9:g.(?41903723)(41903850_?)del	Pathogenic
1324386	NM_000709.4(BCKDHA):c.78del (p.Gln27fs)	Pathogenic
1395580	NM_000709.4(BCKDHA):c.1028C>G (p.Ser343Ter)	Pathogenic
1406283	NC_000019.9:g.(?41903723)(41916924_?)del	Pathogenic
1455786	NM_000709.4(BCKDHA):c.357_358del (p.Leu119_Tyr120insTer)	Pathogenic
1456714	NM_000709.4(BCKDHA):c.33G>A (p.Trp11Ter)	Pathogenic
1459942	NC_000019.9:g.(?41925030)(41930736_?)del	Pathogenic
166741	NM_000709.4(BCKDHA):c.117dup (p.Arg40fs)	Pathogenic
198433	NM_000709.4(BCKDHA):c.861_868del (p.Gly288fs)	Pathogenic
1996087	NM_000709.4(BCKDHA):c.12_13insGACGGGCGAGGTGGCTCACGCCTGAAATCCCAGCACTATGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGATGGCGGTAGCG (p.Ile5fs)	Pathogenic
2020233	NM_000709.4(BCKDHA):c.699_700del (p.Ile233fs)	Pathogenic
2023162	NM_000709.4(BCKDHA):c.41del (p.Asn14fs)	Pathogenic
203638	NM_000709.4(BCKDHA):c.661_664del (p.Tyr221fs)	Pathogenic
204377	NM_000709.4(BCKDHA):c.844G>C (p.Asp282His)	Pathogenic
204380	NM_000709.4(BCKDHA):c.470A>C (p.Gln157Pro)	Pathogenic
2098463	NM_000709.4(BCKDHA):c.659del (p.Ala220fs)	Pathogenic
2104559	NM_000709.4(BCKDHA):c.277G>T (p.Glu93Ter)	Pathogenic
2230997	NM_000709.4(BCKDHA):c.568C>T (p.Gln190Ter)	Pathogenic
224072	NM_000709.4(BCKDHA):c.940C>T (p.Arg314Ter)	Pathogenic
2423349	NC_000019.9:g.(?41916532)(41920072_?)del	Pathogenic
2680126	NM_000709.4(BCKDHA):c.529C>T (p.Gln177Ter)	Pathogenic
2698396	NM_000709.4(BCKDHA):c.644_645del (p.Gln215fs)	Pathogenic
2706056	NM_000709.4(BCKDHA):c.319A>T (p.Lys107Ter)	Pathogenic
2782918	NM_000709.4(BCKDHA):c.796_797delinsT (p.Asn266fs)	Pathogenic
2808947	NM_000709.4(BCKDHA):c.1137del (p.Lys380fs)	Pathogenic
2826260	NM_000709.4(BCKDHA):c.318C>G (p.Tyr106Ter)	Pathogenic

SpliceAI

1310 predictions. Top by Δscore:

Variant	Effect	Δscore
19:41410817:G:GG	donor_gain	1.0000
19:41411005:GGCAG:G	donor_gain	1.0000
19:41411006:GCAG:G	donor_gain	1.0000
19:41411006:GCAGG:G	donor_gain	1.0000
19:41411007:CAGG:C	donor_loss	1.0000
19:41411008:AGG:A	donor_loss	1.0000
19:41411010:G:GC	donor_loss	1.0000
19:41411011:T:G	donor_loss	1.0000
19:41414155:CAG:C	donor_loss	1.0000
19:41414156:AG:A	donor_loss	1.0000
19:41414157:GGTA:G	donor_loss	1.0000
19:41414158:G:GA	donor_loss	1.0000
19:41414158:GT:G	donor_loss	1.0000
19:41414159:T:A	donor_loss	1.0000
19:41414159:T:G	donor_loss	1.0000
19:41419129:TCCTA:T	acceptor_loss	1.0000
19:41419130:CCTA:C	acceptor_loss	1.0000
19:41419131:CTA:C	acceptor_loss	1.0000
19:41419132:TAGG:T	acceptor_loss	1.0000
19:41419132:TAGGT:T	acceptor_loss	1.0000
19:41419133:A:AG	acceptor_gain	1.0000
19:41419133:A:T	acceptor_loss	1.0000
19:41419133:AG:A	acceptor_gain	1.0000
19:41419133:AGGT:A	acceptor_gain	1.0000
19:41419134:G:A	acceptor_loss	1.0000
19:41419134:G:GA	acceptor_gain	1.0000
19:41419134:GG:G	acceptor_gain	1.0000
19:41419134:GGT:G	acceptor_gain	1.0000
19:41419134:GGTG:G	acceptor_gain	1.0000
19:41419134:GGTGT:G	acceptor_gain	1.0000

AlphaMissense

2921 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:41410980:G:C	D116H	1.000
19:41410981:A:C	D116A	1.000
19:41410981:A:T	D116V	1.000
19:41410990:T:C	L119P	1.000
19:41410998:T:C	S122P	1.000
19:41411005:G:C	R124P	1.000
19:41414053:G:C	R127P	1.000
19:41414061:T:C	F130L	1.000
19:41414062:T:C	F130S	1.000
19:41414063:C:A	F130L	1.000
19:41414063:C:G	F130L	1.000
19:41414080:G:A	G136D	1.000
19:41414080:G:T	G136V	1.000
19:41414103:A:C	S144R	1.000
19:41414105:T:A	S144R	1.000
19:41414105:T:G	S144R	1.000
19:41414145:T:C	Y158H	1.000
19:41414149:G:C	R159P	1.000
19:41419222:T:C	M191T	1.000
19:41422226:G:C	G237R	1.000
19:41422226:G:T	G237C	1.000
19:41422227:G:A	G237D	1.000
19:41422227:G:T	G237V	1.000
19:41422232:G:A	G239R	1.000
19:41422232:G:C	G239R	1.000
19:41422232:G:T	G239W	1.000
19:41422233:G:A	G239E	1.000
19:41422241:A:C	S242R	1.000
19:41422243:T:A	S242R	1.000
19:41422243:T:G	S242R	1.000

dbSNP variants (sampled 300 via entrez): RS1000179910 (19:41401665 G>T), RS1000191964 (19:41402497 T>G), RS1000244281 (19:41402187 A>G), RS1000253518 (19:41401314 G>A), RS1000486088 (19:41424137 G>C), RS1000806299 (19:41397712 C>T), RS1000927921 (19:41418475 T>C), RS1000979071 (19:41406209 G>A), RS1000992342 (19:41399951 A>G), RS1001009976 (19:41405920 A>C), RS1001059783 (19:41418643 G>A,T), RS1001113078 (19:41424192 C>T), RS1001257827 (19:41402865 T>C), RS1001407346 (19:41419144 T>C), RS1001468994 (19:41402632 A>T)

Disease associations

OMIM: gene MIM:608348 | disease phenotypes: MIM:248600

GenCC curated gene-disease

Disease	Classification	Inheritance
maple syrup urine disease	Definitive	Autosomal recessive
maple syrup urine disease type 1A	Definitive	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 1A	Definitive	AR

Mondo (7): maple syrup urine disease (MONDO:0009563), maple syrup urine disease type 1A (MONDO:0023691), intellectual disability (MONDO:0001071), 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 (2): Maple syrup urine disease (Orphanet:511), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000738	Hallucinations
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001507	Growth abnormality
HP:0001733	Pancreatitis
HP:0001943	Hypoglycemia
HP:0001946	Ketosis
HP:0002013	Vomiting
HP:0002181	Cerebral edema
HP:0003128	Lactic acidosis
HP:0008344	Elevated circulating branched chain amino acid concentration
HP:0008872	Feeding difficulties in infancy
HP:0031796	Recurrent
HP:0033155	Elevated circulating L-alloisoleucine concentration
HP:0410066	Increased level of hippuric acid in urine
HP:4000207	Reduced branched-chain alpha-keto acid dehydrogenase activity in cultured fibroblasts
HP:6000124	Positive 2,4-dinitrophenylhydrazine urine test

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002647_164	Height	2.000000e-21
GCST008839_277	Height	4.000000e-16

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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

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

Chemical	Actions (top 5)	PubMed papers
Tunicamycin	increases expression	2
FR900359	increases phosphorylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
gossypol acetic acid	decreases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, affects methylation	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Fluorouracil	affects expression	1
Ivermectin	decreases expression	1
Oxygen	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	increases phosphorylation	1
Tretinoin	increases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases expression	1

Cellosaurus cell lines

12 cell lines: 6 finite cell line, 3 transformed cell line, 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_AD59	GM00649	Finite cell line	Male
CVCL_AD60	GM00650	Finite cell line	Male
CVCL_AD61	GM00651	Finite cell line	Female
CVCL_AD62	GM01099	Finite cell line	Female
CVCL_AD65	GM02327	Finite cell line	Female
CVCL_B2SP	Abcam HEK293T BCKDHA KO	Transformed cell line	Female
CVCL_B5JL	HAP1 BCKDHA (-) 2	Cancer cell line	Male
CVCL_D513	GM01654	Finite cell line	Female
CVCL_D514	GM01655	Transformed cell line	Female
CVCL_D6YA	GM28746	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
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
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability