PDHX

Summary

PDHX (pyruvate dehydrogenase complex component X, HGNC:21350) is a protein-coding gene on chromosome 11p13, encoding Pyruvate dehydrogenase protein X component, mitochondrial (O00330). Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.

The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 8050 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 658 total — 21 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 108
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003477

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21350
Approved symbol	PDHX
Name	pyruvate dehydrogenase complex component X
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	E3BP, proX, PDX1, OPDX, DLDBP
Ensembl gene	ENSG00000110435
Ensembl biotype	protein_coding
OMIM	608769
Entrez	8050

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000227868, ENST00000430469, ENST00000448838, ENST00000477173, ENST00000526309, ENST00000532159, ENST00000533262, ENST00000533550, ENST00000885497, ENST00000885498, ENST00000885499, ENST00000885500, ENST00000885501, ENST00000885502, ENST00000885503, ENST00000952501, ENST00000952502, ENST00000952503, ENST00000952504, ENST00000952505, ENST00000952506, ENST00000952507

RefSeq mRNA: 3 — MANE Select: NM_003477 NM_001135024, NM_001166158, NM_003477

CCDS: CCDS44569, CCDS53616, CCDS7896

Canonical transcript exons

ENST00000227868 — 11 exons

Exon	Start	End
ENSE00000710371	34978124	34978182
ENSE00000710373	34984570	34984728
ENSE00000824440	34916618	34916815
ENSE00001150220	34966640	34966814
ENSE00001150226	34960420	34960518
ENSE00001150231	34957384	34957583
ENSE00001150239	34947506	34947606
ENSE00001330369	34970139	34970286
ENSE00002154149	34994914	34996128
ENSE00003504723	34992315	34992379
ENSE00003548956	34931404	34931484

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1974 / max 258.3651, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113750	24.3445	1816
113749	0.7960	374
113751	0.0568	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	97.44	gold quality
heart right ventricle	UBERON:0002080	97.36	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.19	gold quality
left ventricle myocardium	UBERON:0006566	97.02	gold quality
vastus lateralis	UBERON:0001379	96.67	gold quality
diaphragm	UBERON:0001103	96.59	gold quality
skeletal muscle tissue	UBERON:0001134	96.48	gold quality
quadriceps femoris	UBERON:0001377	96.46	gold quality
deltoid	UBERON:0001476	96.24	gold quality
muscle organ	UBERON:0001630	96.20	gold quality
skeletal muscle organ	UBERON:0014892	96.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.08	gold quality
muscle of leg	UBERON:0001383	96.06	gold quality
gastrocnemius	UBERON:0001388	95.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.66	gold quality
adrenal tissue	UBERON:0018303	95.51	gold quality
muscle tissue	UBERON:0002385	95.50	gold quality
cardiac ventricle	UBERON:0002082	95.17	gold quality
heart left ventricle	UBERON:0002084	95.13	gold quality
tibialis anterior	UBERON:0001385	95.08	gold quality
myocardium	UBERON:0002349	94.99	gold quality
triceps brachii	UBERON:0001509	94.74	gold quality
body of tongue	UBERON:0011876	94.73	gold quality
calcaneal tendon	UBERON:0003701	94.57	gold quality
gluteal muscle	UBERON:0002000	94.30	gold quality
heart	UBERON:0000948	93.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.21	gold quality
apex of heart	UBERON:0002098	92.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.31	gold quality
cardiac atrium	UBERON:0002081	92.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.42
E-MTAB-4850	no	454.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
GCG	Repression
INS	Activation

Upstream regulators (CollecTRI, top): PAX6

miRNA regulators (miRDB)

63 targeting PDHX, 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-5692A	100.00	74.40	6850
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-33A-3P	99.70	70.27	3362

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 13)

• determination that PDH and complex III exist at a steady-state ratio of 1:100, 1:128 and 1:202 in HeLa cell extracts, fibroblast mitochondria and heart tissue mitochondria, respectively (PMID:12372595)
• model of the pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and binding of the E1 and E3 components (PMID:14638692)
• specificity of pairing for human E3BP with E3 from its subcomplex structure to be most likely due to conformational rigidity of the binding fragment of the E3-binding domain of E3BP and its exquisite amino acid match with the E3 target interface (PMID:16263718)
• A cluster of disease-causing E3 mutations located near the center of the E3BD/E3 interface prevents the efficient recruitment of these E3 variants by E3BP into the PDC, leading to the dysfunction of the PDC catalytic machine. (PMID:16442803)
• These data provide an additional case of E3BP deficiency with a unique and previously unreported deletion in the PDHX gene. (PMID:16566017)
• Despite the presence of antibodies reactive with PDC-E3BP in the majority of primary biliary cirrhosis (PBC) patients this self-protein is not a dominant T-cell autoantigen in PBC. (PMID:16629643)
• genetic association with systemic lupus erythematosus to a haplotype between PDHX and CD44 was established. (PMID:21194677)
• New mutation in PDHX gene found in two unrelated patients with Pyruvate dehydrogenase deficiency. (PMID:22766002)
• MiR-26a regulates glucose metabolism of colorectal cancer cells by direct targeting PDHX. (PMID:24935220)
• We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. (PMID:25087164)
• PDHX is a functional target of miR-27b and that this interaction has consequential effects on cell metabolism which facilitate cell growth and progression in breast cancer. (PMID:30012170)
• Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma. (PMID:33964039)
• Cuproptosis-related gene PDHX and heat stress-related HSPD1 as potential key drivers associated with cell stemness, aberrant metabolism and immunosuppression in esophageal carcinoma. (PMID:36889194)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdhx	ENSDARG00000051756
mus_musculus	Pdhx	ENSMUSG00000010914
rattus_norvegicus	Pdhx	ENSRNOG00000006947
caenorhabditis_elegans		WBGENE00007824

Paralogs (3): DLST (ENSG00000119689), DBT (ENSG00000137992), DLAT (ENSG00000150768)

Protein

Protein identifiers

Pyruvate dehydrogenase protein X component, mitochondrial — O00330 (reviewed: O00330)

Alternative names: Dihydrolipoamide dehydrogenase-binding protein of pyruvate dehydrogenase complex, E3-binding protein, Lipoyl-containing pyruvate dehydrogenase complex component X, proX

All UniProt accessions (5): O00330, A0A8C8MSB2, E9PLU0, E9PRI6, H0YD97

UniProt curated annotations — full annotation on UniProt →

Function. Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. This specific binding is essential for a functional PDH complex.

Subunit / interactions. Part of the inner core of the multimeric pyruvate dehydrogenase complex that is composed of about 48 DLAT and 12 PDHX molecules. This core binds multiple copies of pyruvate dehydrogenase (subunits PDH1A and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). Interacts with SIRT4. Interacts with DLD.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Delipoylated at Lys-97 by SIRT4, delipoylation decreases the PHD complex activity.

Disease relevance. Pyruvate dehydrogenase E3-binding protein deficiency (PDHXD) [MIM:245349] A metabolic disorder characterized by decreased activity of the pyruvate dehydrogenase complex without observable reduction in the activities of enzymes E1, E2, or E3. Clinical features include hypotonia and psychomotor retardation. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the 2-oxoacid dehydrogenase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O00330-1	1	yes
O00330-2	2
O00330-3	3

RefSeq proteins (3): NP_001128496, NP_001159630, NP_003468* (*=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
IPR045257	E2/Pdx1	Family

Pfam: PF00198, PF00364, PF02817

Enzyme classification (BRENDA):

• EC 1.2.1.104 — pyruvate dehydrogenase system (BRENDA: 46 organisms, 32 substrates, 100 inhibitors, 83 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PYRUVATE	0.0002–1	44
NAD+	0.01–0.27	14
COA	0.0005–0.61	12
THIAMINE DIPHOSPHATE	0.0016–0.05	3
2-OXOBUTANOATE	1.35	1
2-OXOBUTYRATE	1.66	1
2-OXOISOVALERATE	1.27	1
COENZYME A	0.003	1
HYDROXYETHYL THIAMINE DIPHOSPHATE	0.0082	1
LIPOYL DOMAIN	0.02	1
N-ACETYL-GDLLAEIETDK(LIPOYL)-ATIG-AMIDE	15	1
N-TERMINAL LIPOYL DOMAIN	0.052	1
N-ACETYL-GDLLAEIETDK(LIPOYLATED)ATIG-AMIDE	—	0

UniProt features (49 total): mutagenesis site 15, strand 8, helix 5, modified residue 4, sequence variant 3, sequence conflict 3, compositionally biased region 3, splice variant 2, domain 2, region of interest 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2F60	X-RAY DIFFRACTION	1.55
2F5Z	X-RAY DIFFRACTION	2.18
1ZY8	X-RAY DIFFRACTION	2.59
6H60	ELECTRON MICROSCOPY	6
2DNC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00330-F1	77.13	0.41

Functional residue map

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

Post-translational modifications (4): 194, 196, 394, 97

Mutagenesis-validated functional residues (15):

Position	Phenotype
183	strongly decreased dld binding.
185	strongly decreased dld binding.
186	strongly decreased dld binding.
187	strongly decreased dld binding.
189	strongly decreased dld binding.
190	decreased dld binding.
190	moderately decreased interaction with dld.
193	strongly decreased dld binding.
208	strongly decreased dld binding.
208	decreased interaction with dld.
210	strongly decreased dld binding.
210	decreased interaction with dld.
213	strongly decreased dld binding.
214	strongly decreased dld binding.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9861559	PDH complex synthesizes acetyl-CoA from PYR

MSigDB gene sets: 595 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, PID_HNF3B_PATHWAY, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_INSULIN_SECRETION

GO Biological Process (1): pyruvate decarboxylation to acetyl-CoA (GO:0006086)

GO Molecular Function (4): dihydrolipoyllysine-residue acetyltransferase activity (GO:0004742), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), plasma membrane (GO:0005886), pyruvate dehydrogenase complex (GO:0045254)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dihydrolipoyl dehydrogenase (NADH) activity	1
pyruvate dehydrogenase (acetyl-transferring) activity	1
dihydrolipoyllysine-residue acetyltransferase activity	1
acetyl-CoA biosynthetic process	1
pyruvate metabolic process	1
aerobic respiration	1
S-acetyltransferase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
transferase activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
alpha-ketoacid dehydrogenase complex	1
acetyltransferase complex	1

Protein interactions and networks

STRING

3326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDHX	PDHB	P11177	997
PDHX	DLD	P09622	995
PDHX	PDHA1	P08559	988
PDHX	PDP2	Q9P2J9	970
PDHX	PDP1	Q9P0J1	937
PDHX	DLAT	P10515	887
PDHX	PDHA2	P29803	738
PDHX	PDK2	Q15119	662
PDHX	OGDH	Q02218	616
PDHX	LIPT1	Q9Y234	609
PDHX	PDK3	Q15120	588
PDHX	APIP	Q96GX9	566
PDHX	PDPR	Q8NCN5	557
PDHX	LIPT2	A6NK58	543
PDHX	LIAS	O43766	538

IntAct

67 interactions, top by confidence:

A	B	Type	Score
PDHX	DLD	psi-mi:“MI:0407”(direct interaction)	0.880
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
PDHX	DLD	psi-mi:“MI:0915”(physical association)	0.880
DLD	PDHX	psi-mi:“MI:0407”(direct interaction)	0.880
AGTRAP	PDHX	psi-mi:“MI:0915”(physical association)	0.740
PDHX	AGTRAP	psi-mi:“MI:0915”(physical association)	0.740
SIRT4	PDHX	psi-mi:“MI:0403”(colocalization)	0.560
SIRT4	PDHX	psi-mi:“MI:0914”(association)	0.560
SIRT4	PDHX	psi-mi:“MI:0212”(lipoprotein cleavage reaction)	0.560
PDHX	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
HSCB	PDHX	psi-mi:“MI:0915”(physical association)	0.550
PDHX	MTIF2	psi-mi:“MI:0914”(association)	0.530
PDK3	PDHX	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
STAT5A	PDHX	psi-mi:“MI:0914”(association)	0.530
PCNA	PDHX	psi-mi:“MI:0915”(physical association)	0.370
DLAT	PDHX	psi-mi:“MI:0915”(physical association)	0.370
ACTN1	PDHX	psi-mi:“MI:0915”(physical association)	0.370
EWSR1	PDHX	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
STAT5B	PDHX	psi-mi:“MI:0914”(association)	0.350
STAT5A	R3HDM2	psi-mi:“MI:0914”(association)	0.350

BioGRID (149): AGTRAP (Two-hybrid), PDHX (Affinity Capture-RNA), EP300 (Reconstituted Complex), PDHX (Affinity Capture-Western), EP300 (Affinity Capture-Western), NEUROD1 (Affinity Capture-Western), PDHX (Affinity Capture-Western), PDHX (Affinity Capture-MS), PDHX (Affinity Capture-MS), PDHX (Affinity Capture-MS), PDHX (Two-hybrid), PDHX (Affinity Capture-MS), PDHX (Co-fractionation), PDHX (Two-hybrid), PDHX (Affinity Capture-MS)

ESM2 similar proteins: A0A0D2Y5A7, G0S4X6, O00330, O59816, O94681, P08461, P0CN60, P0CN61, P10515, P11141, P11179, P11180, P11961, P12695, P19262, P20285, P21883, P22439, P35489, P36413, P36957, P37900, P45118, P65634, P86197, P9WIS6, P9WIS7, Q01205, Q0WQF7, Q19749, Q1RHI5, Q1RJT3, Q23571, Q4ULG1, Q59638, Q5B0C0, Q5M729, Q5Y223, Q869Y7, Q8BKZ9

Diamond homologs: A0A0D2Y5A7, G0S4X6, G0S5Q0, O00330, O31550, O59816, O66113, O66119, O94709, P06959, P08461, P10515, P11180, P12695, P16263, P16451, P19262, P20285, P20708, P22439, P36413, P36957, P45118, P47514, P52993, P65635, P65636, P75392, P86197, Q0WQF7, Q19749, Q1RJT3, Q49XM4, Q4UKI7, Q4ULG1, Q59098, Q59695, Q59821, Q5HGY9, Q5M729

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PDHX	“down-regulates quantity by repression”	GCG	“transcriptional regulation”
PDHX	“up-regulates quantity by expression”	INS	“transcriptional regulation”
PDHX	“down-regulates activity”	PAX6	binding
PDHX	“down-regulates activity”	CDX2	binding
PDHX	“form complex”	PDH	binding
FOXO1	“down-regulates quantity by repression”	PDHX	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
Regulation of pyruvate dehydrogenase (PDH) complex	6	122.4×	1e-09
Signaling by Retinoic Acid	5	58.3×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	27
Uncertain significance	315
Likely benign	150
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1459035	NC_000011.9:g.(?34969033)(34969173_?)del	Pathogenic
2021106	NM_003477.3(PDHX):c.921_922del (p.Cys307_Asp308delinsTer)	Pathogenic
2112	NM_003477.3(PDHX):c.965_1023del (p.Asp322fs)	Pathogenic
2114	NM_003477.3(PDHX):c.641+1G>A	Pathogenic
2115	NM_003477.3(PDHX):c.1024-1G>A	Pathogenic
2116	NM_003477.3(PDHX):c.620del (p.Pro207fs)	Pathogenic
2117	NG_013368.1:g.33923_80418delins[DQ831669.1:28435_34519]	Pathogenic
2118	NM_003477.3(PDHX):c.742C>T (p.Gln248Ter)	Pathogenic
2119	NM_003477.3(PDHX):c.1183-3088_1247+760del	Pathogenic
2158386	NM_003477.3(PDHX):c.1231C>T (p.Gln411Ter)	Pathogenic
2424684	NC_000011.9:g.(?34978911)(34979150_?)del	Pathogenic
30124	NM_000209.4(PDX1):c.533A>G (p.Glu178Gly)	Pathogenic
3244749	NC_000011.9:g.(?34938203)(34938382_?)del	Pathogenic
3341997	NM_003477.3(PDHX):c.443del (p.Gly148fs)	Pathogenic
3599570	NM_003477.3(PDHX):c.1182+2T>C	Pathogenic
3631223	NM_003477.3(PDHX):c.250del (p.Ala83_Val84insTer)	Pathogenic
3679976	NM_003477.3(PDHX):c.1311del (p.Cys438fs)	Pathogenic
3902578	NM_000209.4(PDX1):c.494_497delinsAC (p.Phe165fs)	Pathogenic
650650	NM_003477.3(PDHX):c.850C>T (p.Arg284Ter)	Pathogenic
660921	NM_003477.3(PDHX):c.211G>T (p.Gly71Ter)	Pathogenic
8865	NM_000209.4(PDX1):c.532G>A (p.Glu178Lys)	Pathogenic
1067131	NM_003477.3(PDHX):c.816+1G>A	Likely pathogenic
1198487	NM_003477.3(PDHX):c.1426C>T (p.Arg476Ter)	Likely pathogenic
1509161	NC_000011.9:g.(?34969033)(34969173_?)dup	Likely pathogenic
1722384	NC_000011.9:g.(34953032_34969052)_(34999730_35006116)del	Likely pathogenic
1755049	NM_000209.4(PDX1):c.671_672dup (p.Gln225fs)	Likely pathogenic
2175248	NM_003477.3(PDHX):c.161-2A>G	Likely pathogenic
2229226	NM_003477.3(PDHX):c.1305dup (p.Gln436fs)	Likely pathogenic
2441847	NM_003477.3(PDHX):c.1012dup (p.Val338fs)	Likely pathogenic
2445919	NC_000011.9:g.(34988362_34991685)_(34991834_34999670)del	Likely pathogenic

SpliceAI

2389 predictions. Top by Δscore:

Variant	Effect	Δscore
11:34931397:A:G	acceptor_gain	1.0000
11:34931400:TCA:T	acceptor_loss	1.0000
11:34931401:CAG:C	acceptor_loss	1.0000
11:34931402:A:AG	acceptor_gain	1.0000
11:34931402:AG:A	acceptor_gain	1.0000
11:34931402:AGGT:A	acceptor_gain	1.0000
11:34931403:G:GC	acceptor_gain	1.0000
11:34931403:GG:G	acceptor_gain	1.0000
11:34931403:GGT:G	acceptor_gain	1.0000
11:34931403:GGTG:G	acceptor_gain	1.0000
11:34931480:GGAAG:G	donor_gain	1.0000
11:34931481:GAAGG:G	donor_gain	1.0000
11:34931482:A:T	donor_gain	1.0000
11:34931484:GG:G	donor_loss	1.0000
11:34931486:T:G	donor_loss	1.0000
11:34931490:G:GT	donor_gain	1.0000
11:34947602:TCGTG:T	donor_gain	1.0000
11:34947603:CGTGG:C	donor_loss	1.0000
11:34947604:GTG:G	donor_gain	1.0000
11:34947605:TGG:T	donor_loss	1.0000
11:34947607:G:GA	donor_loss	1.0000
11:34947607:G:GG	donor_gain	1.0000
11:34947608:TAA:T	donor_loss	1.0000
11:34957381:TAG:T	acceptor_loss	1.0000
11:34957382:AGG:A	acceptor_loss	1.0000
11:34957584:G:GG	donor_gain	1.0000
11:34957584:GTGA:G	donor_loss	1.0000
11:34957585:T:G	donor_loss	1.0000
11:34960515:AAGA:A	donor_gain	1.0000
11:34960517:GA:G	donor_gain	1.0000

AlphaMissense

3220 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:34931469:T:A	W76R	0.998
11:34931469:T:C	W76R	0.998
11:34960440:C:A	A188D	0.997
11:34947556:G:C	A98P	0.995
11:34931471:G:C	W76C	0.994
11:34931471:G:T	W76C	0.994
11:34947535:T:C	C91R	0.994
11:34947555:A:C	K97N	0.994
11:34947555:A:T	K97N	0.994
11:34947554:A:T	K97I	0.993
11:34960430:A:C	S185R	0.993
11:34960432:T:A	S185R	0.993
11:34960432:T:G	S185R	0.993
11:34957427:G:A	G129D	0.991
11:34966644:G:C	A216P	0.991
11:34966645:C:A	A216D	0.991
11:34970184:G:C	A288P	0.991
11:34931470:G:C	W76S	0.990
11:34960516:A:C	K213N	0.990
11:34960516:A:T	K213N	0.990
11:34947596:C:A	A111D	0.989
11:34970185:C:A	A288D	0.989
11:34931454:G:A	G71R	0.988
11:34931454:G:C	G71R	0.988
11:34960437:C:A	A187D	0.988
11:34947542:T:A	I93N	0.987
11:34957426:G:C	G129R	0.987
11:34947548:C:T	T95I	0.985
11:34947593:T:C	L110S	0.985
11:34960439:G:C	A188P	0.985

dbSNP variants (sampled 300 via entrez): RS1000074978 (11:34930471 C>G,T), RS1000108098 (11:34988290 A>G,T), RS1000212224 (11:34954989 T>G), RS1000224716 (11:34919974 A>T), RS1000255829 (11:34919757 C>T), RS1000293621 (11:34951877 C>A), RS1000371620 (11:34946735 T>TC), RS1000462451 (11:34914972 C>A,G), RS1000469315 (11:34945049 T>A), RS1000494767 (11:34924949 G>T), RS1000504078 (11:34929039 C>T), RS1000568000 (11:34968736 A>G,T), RS1000568543 (11:34989334 A>G), RS1000585169 (11:34962340 G>A), RS1000586662 (11:34918556 A>T)

Disease associations

OMIM: gene MIM:608769 | disease phenotypes: MIM:125853, MIM:606392, MIM:125850, MIM:606391, MIM:260370, MIM:245349, MIM:312170, MIM:606176

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate dehydrogenase E3-binding protein deficiency	Definitive	Autosomal recessive
maturity-onset diabetes of the young type 4	Definitive	Autosomal dominant
pancreatic agenesis 1	Strong	Autosomal recessive
permanent neonatal diabetes mellitus	Strong	Autosomal recessive
pancreatic agenesis	Supportive	Autosomal recessive
maturity-onset diabetes of the young	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
monogenic diabetes	Moderate	AD
mitochondrial disease	Definitive	AR
pancreatic agenesis 1	Definitive	AR

Mondo (11): type 2 diabetes mellitus (MONDO:0005148), maturity-onset diabetes of the young type 4 (MONDO:0011667), maturity-onset diabetes of the young (MONDO:0018911), pancreatic agenesis 1 (MONDO:0024547), pyruvate dehydrogenase E3-binding protein deficiency (MONDO:0009503), monogenic diabetes (MONDO:0015967), pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717), mitochondrial disease (MONDO:0044970), permanent neonatal diabetes mellitus (MONDO:0100164), neonatal diabetes mellitus (MONDO:0016391), pancreatic agenesis (MONDO:0009832)

Orphanet (8): Partial pancreatic agenesis (Orphanet:2805), MODY (Orphanet:552), Pyruvate dehydrogenase E3-binding protein deficiency (Orphanet:255182), Rare genetic diabetes mellitus (Orphanet:183625), Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243), Mitochondrial disease (Orphanet:68380), Isolated permanent neonatal diabetes mellitus (Orphanet:99885), Neonatal diabetes mellitus (Orphanet:224)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000488	Retinopathy
HP:0000496	Abnormality of eye movement
HP:0000648	Optic atrophy
HP:0000767	Pectus excavatum
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000857	Neonatal insulin-dependent diabetes mellitus
HP:0000956	Acanthosis nigricans
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000253_2	Attention deficit hyperactivity disorder and conduct disorder	9.000000e-06
GCST001527_6	Fasting blood glucose (BMI interaction)	5.000000e-10
GCST002553_1	Pancreatic cancer	2.000000e-09
GCST002991_12	Pancreatic cancer	2.000000e-07
GCST004206_15	Fasting plasma glucose	5.000000e-10
GCST004206_6	Fasting plasma glucose	1.000000e-08
GCST004487_4	Peak insulin response	3.000000e-06
GCST004575_1	Acute insulin response	4.000000e-07
GCST005186_4	Fasting blood glucose	9.000000e-10
GCST005434_9	Pancreatic cancer	5.000000e-14
GCST005752_127	Systemic lupus erythematosus	1.000000e-08
GCST005951_4	Body mass index	2.000000e-08
GCST006002_14	Blood sugar levels	9.000000e-10
GCST006444_5	Bone mineral density (hip)	5.000000e-07
GCST006462_36	Uterine fibroids	2.000000e-09
GCST006979_788	Heel bone mineral density	9.000000e-53
GCST007400_67	Systemic lupus erythematosus	1.000000e-06
GCST007899_17	Fasting blood glucose	5.000000e-08
GCST007954_24	Glycated hemoglobin levels	5.000000e-07
GCST008362_49	Birth weight	8.000000e-09
GCST009158_2	Uterine fibroids	7.000000e-14
GCST009379_313	Type 2 diabetes	5.000000e-06
GCST009379_314	Type 2 diabetes	3.000000e-08
GCST90000047_186	Age at first sexual intercourse	5.000000e-09
GCST90011898_20	Alanine aminotransferase levels	4.000000e-12

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008000	peak insulin response measurement
EFO:0006831	acute insulin response measurement
EFO:0004468	glucose measurement
EFO:0007702	hip bone mineral density
EFO:0009270	heel bone mineral density
EFO:0004541	HbA1c measurement
EFO:0004344	birth weight
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C563425	Diabetes Mellitus, Permanent Neonatal (supp.)
C562772	Mason-Type Diabetes (supp.)
C563451	Maturity-Onset Diabetes of the Young, Type 4 (supp.)
C564908	Pancreatic Agenesis, Congenital (supp.)
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)
C565447	Pyruvate Dehydrogenase E3-Binding Protein Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067060 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	Kd	48.19	nM	CHEMBL3752910
7.32	ED50	48.19	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148962: Binding affinity to human PDHX incubated for 45 mins by Kinobead based pull down assay	kd	0.0482	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Air Pollutants	increases abundance, decreases expression	3
Acetaminophen	decreases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases methylation	2
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression, increases abundance	1
tamibarotene	affects expression	1
deguelin	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	decreases expression, decreases reaction	1
Allergens	affects cotreatment, increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Coal	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	increases 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
CHEMBL5652004	Binding	Binding affinity to human PDHX incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PN	Abcam K-562 PDHX KO	Cancer cell line	Female
CVCL_D2L9	Abcam Raji PDHX KO	Cancer cell line	Male
CVCL_WQ24	Abcam Jurkat PDHX KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02624817	PHASE4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	PHASE4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes