PNPO
protein-codingpyridoxamine 5'-phosphate oxidase
Gene summary
The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012407
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012407
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012407
Submitter: ClinGen
PNPO was first reported in relation to autosomal recessive pyridoxal phosphate-responsive seizures in 2005 (Mills et al., 2005, PMID: 15772097). Pyridoxal phosphate-responsive seizures (MONDO: 0012407) is characterized by neonatal-onset severe seizures commonly observed within the first several hours to days of life, and subsequent encephalopathy. Developmental delay, intellectual disability, hypotonia, erratic eye movements, etc are also observed in patients with variants in PNPO. Fourteen variants (missense and frameshift) that have been reported in twenty-six probands in nine publications (PMIDs: 15772097, 23430561, 18485777, 24266778, 24658933, 24645144, 25296925, 28133863, 28985901) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and a rescue (PMIDs: 15772097, 31261385, 31616300, 31759955). Chi et al., 2019 (PMID: 31261385) demonstrated cell-type specific expression in sugarlethal drosophila with the previously identified variant c.95C>A is a valid model for PNPO-deficiency induced epilepsy. Ciapaite et al., 2020 (PMID: 31759955) used CRISPR/Cas9 gene editing to generate Pnpo-deficient zebrafish in which locomotion analysis demonstrated that these zebrafish developed seizures and only 38% survived. Even though the default points for animal models is 2 points, the ClinGen Epilepsy GCEP has decided to downgrade evidence in Chi et al., 2019 and Ciapaite et al., 2020 to 1 point because they are non-mammalian model systems. An additional line of experimental evidence (rescue) was published by Chen et al., 2019 (PMID: 31616300). In summary, PNPO is definitively associated with autosomal recessive pyridoxal phosphate-responsive seizures. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 12/15/2020 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0012407
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012407
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical; Neurologic
Rationale: Individuals may manifest with severe seizures starting in the immediate neonatal period (or even before birth), and medical treatment (with pyridoxal phosphate) can be effective as an antiepileptic agent
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PNPO variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018129.4. 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 | 2 | 89 | 1 | 92 | ||
| missense | 4 | 14 | 120 | 2 | 140 | |
| nonsense | 4 | 3 | 7 | |||
| start loss | 2 | 2 | ||||
| frameshift | 5 | 3 | 1 | 9 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | 2 | 12 | ||
| Total | 18 | 27 | 125 | 91 | 1 | 262 |
Highest pathogenic variant AF is 0.00022133066
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060599.1 | 7 | MANE Select | |
| Ensembl | ENSP00000493302.2 | 7 | MANE Select | |
| RefSeq | NP_001423234.1 | 6 | Standard | |
| Ensembl | ENSP00000225573.5 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vitamin B6 metabolism - Homo sapiens (human)
- Hypophosphatasia
- Vitamin B6 Metabolism
- Selenium Micronutrient Network
- Vitamin B6-dependent and responsive disorders
Biological Process
- pyridoxine biosynthetic process
- vitamin B6 metabolic process
- pyridoxal phosphate biosynthetic process
- oxidation-reduction process
Molecular Function
- pyridoxamine-phosphate oxidase activity
- protein binding
- FMN binding
- pyridoxal phosphate binding
- protein homodimerization activity
Cellular Component
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000225573
- Coding exons
- 7
- Length
- 6783
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125748
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.781 | 120 | 147 | 0.818 | 0.00000873 | 1685 |
| Missense (PolyPhen) | 63 | 59.493 | 1.0589 | 654 | ||
| Synonymous | 0.371 | 48 | 51.4 | 0.934 | 0.00000253 | 500 |
| Loss of Function | 0.334 | 13 | 14.4 | 0.905 | 6.95e-7 | 159 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the oxidation of either pyridoxine 5'- phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal 5'-phosphate (PLP). {ECO:0000269|PubMed:12824491}.;
- Disease
- DISEASE: Pyridoxine-5'-phosphate oxidase deficiency (PNPOD) [MIM:610090]: The main feature of neonatal epileptic encephalopathy is the onset within hours of birth of a severe seizure disorder that does not respond to anticonvulsant drugs and can be fatal. Seizures can cease with the administration of PLP, being resistant to treatment with pyridoxine,. {ECO:0000269|PubMed:15772097, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.236
Intolerance Scores
- LoFtool
- 0.652
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.994
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |