PDHX
protein-codingpyruvate dehydrogenase complex component X, the group of Pyruvate dehydrogenase complex|MicroRNA protein coding host genes
Gene summary
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.[provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~104.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between PDHX and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The PDHX gene encodes the E3 binding protein of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. The PDHX gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2003 (PMID: 12557299). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants identified in five cases in five publications (PMIDs: 12557299, 14518830, 15303005, 16566017, 25087164). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and functional alteration in patient cells (PMIDs: 27977873, 21139605, 14518830). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the gene-disease association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 13, 2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009503
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *PDHX* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 17, 2024. The *PDHX* gene encodes the E3 binding protein of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, and is thus the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. *PDHX* was first reported in relation to autosomal recessive primary mitochondrial disease in 1997 (PMID: 9399911). While various names have been given to the constellation of features seen in those with *PDHX*-related disorders, including pyruvate dehydrogenase complex deficiency or PDCD, pathogenic variants in this gene ultimately cause a primary mitochondrial disease. Therefore, the PDHX phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *PDHX* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on July 13, 2020 (SOP V7), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation. Evidence supporting the relationship between *PDHX* and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes seven variants identified in six unrelated probands in six publications (PMIDs: 12557299, 14518830, 15303005, 16566017, 25087164, 27343776). Variants reported include nonsense, splicing, and frameshift. There is a Roma founder variant, NM_003477.3:c.1336C>T (p.Arg446Ter), and a Moroccan founder variant (NM_003477.3:c.1182+2T>C (p.Ile386SerfsTer13). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Age of onset ranged from the first days of life to later in childhood, with some individuals living well into adulthood. Clinical features in affected individuals include neonatal lactic acidosis, LSS, seizures, spasticity, agenesis of the corpus callosum, cerebral atrophy, vomiting, and optic atrophy. PDC enzyme activity was reduced in fibroblasts. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of the E3 binding protein in supporting PDC activity, and functional alteration in patient cells (PMIDs: 14518830, 11935326, 20002125). In summary, there is definitive evidence to support the relationship between *PDHX* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 17, 2024 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: Medical and dietary treatment (eg, ketogenic diet) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDHX variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003477.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 54 | 5 | 66 | ||
| missense | 2 | 168 | 17 | 1 | 188 | |
| nonsense | 5 | 7 | 1 | 13 | ||
| start loss | 0 | |||||
| frameshift | 8 | 10 | 2 | 20 | ||
| splice donor/acceptor (+/-2bp) | 5 | 4 | 4 | 13 | ||
| Total | 18 | 23 | 182 | 71 | 6 | 300 |
Highest pathogenic variant AF is 0.000050409577
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003468.2 | 11 | MANE Select | |
| Ensembl | ENSP00000227868.4 | 11 | MANE Select | |
| RefSeq | NP_001128496.2 | 10 | Standard | |
| RefSeq | NP_001159630.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Amino Acid metabolism
- Glycolysis and Gluconeogenesis
- Signal Transduction
- Regulation of pyruvate dehydrogenase (PDH) complex
- Pyruvate metabolism
Biological Process
- mitochondrial acetyl-CoA biosynthetic process from pyruvate
Molecular Function
- protein binding
- transferase activity, transferring acyl groups
- pyruvate dehydrogenase (NAD+) activity
Cellular Component
- mitochondrial matrix
- pyruvate dehydrogenase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000227868
- Coding exons
- 11
- Length
- 104763
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 48
- Defined
- 125748
- p
- 0.000195
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.203 | 289 | 279 | 1.03 | 0.0000147 | 3194 |
| Missense (PolyPhen) | 101 | 97.361 | 1.0374 | 1217 | ||
| Synonymous | -0.152 | 101 | 99.1 | 1.02 | 0.00000513 | 1047 |
| Loss of Function | 2.64 | 11 | 25.4 | 0.434 | 0.00000130 | 292 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.00019 | 0.00019 | rare |
| South Asian | 0.00049 | 0.00046 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:9399911}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.419
Intolerance Scores
- LoFtool
- 0.901
- RVIS EVS
- 0.25
- RVIS percentile EVS
- 69.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.949
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |