GPX4
protein-codingglutathione peroxidase 4, the group of Selenoproteins
Gene summary
The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a 'moonlighting' protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization. [provided by RefSeq, Dec 2018]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009593
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009593
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009593
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009593
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009593
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies (including structural anomalies and arrhythmia), and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GPX4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002085.5. 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 | 26 | 2 | 30 | ||
| missense | 1 | 63 | 2 | 1 | 67 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 4 | 6 | |||
| splice donor/acceptor (+/-2bp) | 4 | 7 | 11 | |||
| Total | 3 | 9 | 72 | 28 | 3 | 115 |
Highest pathogenic variant AF is 0.00005426125
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002076.2 | 7 | MANE Select | |
| Ensembl | ENSP00000346103.7 | 7 | MANE Select | |
| RefSeq | NP_001034936.1 | 7 | Standard | |
| RefSeq | NP_001034937.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gpx4b | Danio rerio | Structure: caudal fin Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glutathione metabolism - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Glutathione metabolism
- Selenium Micronutrient Network
- Folate Metabolism
Biological Process
- chromatin organization
- phospholipid metabolic process
- glutathione metabolic process
- response to oxidative stress
- multicellular organism development
Molecular Function
- peroxidase activity
- glutathione peroxidase activity
- protein binding
- selenium binding
- identical protein binding
Cellular Component
- nucleus
- nuclear envelope
- nucleoplasm
- mitochondrion
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354171
- Coding exons
- 7
- Length
- 2852
- Individuals with no LoFs
- 124695
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 124724
- p
- 0.000116
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.08 | 159 | 125 | 1.27 | 0.00000753 | 1285 |
| Missense (PolyPhen) | 41 | 47.342 | 0.86604 | 495 | ||
| Synonymous | -3.47 | 89 | 55.9 | 1.59 | 0.00000435 | 359 |
| Loss of Function | 0.906 | 8 | 11.3 | 0.709 | 5.33e-7 | 125 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00026 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00078 | 0.00067 | rare |
| Finnish | 0.000093 | 0.000093 | rare |
| European (Non-Finnish) | 0.000063 | 0.000062 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron- dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin- positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T- cell response to viral and parasitic infection by protecting T- cells from ferroptosis and by supporting T-cell expansion (By similarity). {ECO:0000250|UniProtKB:O70325, ECO:0000250|UniProtKB:P36968, ECO:0000269|PubMed:24439385}.;
Intolerance Scores
- LoFtool
- 0.582
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.989