PLG
protein-codingplasminogen
Gene summary
The plasminogen protein encoded by this gene is a serine protease that circulates in blood plasma as an inactive zymogen and is converted to the active protease, plasmin, by several plasminogen activators such as tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562. Plasmin cleavage also releases the angiostatin protein which inhibits angiogenesis. Plasmin degrades many blood plasma proteins, including fibrin-containing blood clots. As a serine protease, plasmin cleaves many products in addition to fibrin such as fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin is inactivated by proteins such as alpha-2-macroglobulin and alpha-2-antiplasmin in addition to inhibitors of the various plasminogen activators. Plasminogen also interacts with plasminogen receptors which results in the retention of plasmin on cell surfaces and in plasmin-induced cell signaling. The localization of plasminogen on cell surfaces plays a role in the degradation of extracellular matrices, cell migration, inflamation, wound healing, oncogenesis, metastasis, myogenesis, muscle regeneration, neurite outgrowth, and fibrinolysis. This protein may also play a role in acute respiratory distress syndrome (ARDS) which, in part, is caused by enhanced clot formation and the suppression of fibrinolysis. Compared to other mammals, the cluster of plasminogen-like genes to which this gene belongs has been rearranged in catarrhine primates. [provided by RefSeq, May 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~51.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009009
Submitter: ClinGen
The relationship between PLG and Hypoplasminogenemia (Dysplasminogenemia and Plasminogen deficiency, type I, included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of September, 2019. PLG was reported in relation to Hypoplasminogenemia as early as 1997 (Schuster et al, 1997, PMID: 9242524; Murata, 1997, PMID: 9375744). At least 11 unique variants including nonsense, splice site, frameshift and missense have been reported in humans. PLG encodes plasminogen, which is secreted as a zymogen and is activated by proteolysis and converted to plasmin and angiostatin. Plasmin is involved in fibrinolysis. Hypoplasminogenemia or congenital plasminogen deficiency is characterized by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature (PMID: 12850227). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 Points): Variants in this gene have been reported in at least 10 probands in 7 publications (PMID: 9834305, 9242524, 10233898, 9375744, 16849641, 9255907, 11477736). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (4.5 points): This gene-disease association is supported by mouse models and in vitro functional assays. The PLG knock-out mouse generated by Bugge et al, (PMID: 7705657) has been shown to recapitulate ligneous conjunctivitis (PMID: 9473227). Plasminogen is involved in fibrinolysis, and the loss of the activity due to PLG variants results in abnormal fibrin deposition in tissues, as observed in individuals with plasminogen deficiency (PMID: 9501859). Plasminogen is largely synthesized in the liver, with expression limited to liver and kidney; however, plasminogen is also shown to be synthesized by the corneal epithelium (PMID: 10215610). Therapeutic administration of Glu-Plasminogen is shown to improve symptoms in individuals with PLG variants and plasminogen deficiency (PMID: 29321155). In summary, PLG is definitively associated with Autosomal Recessive Hypoplasminogenemia. 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 Hemostasis/Thrombosis GCEP on October, 23, 2019 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0009009
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009009
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009009
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009009
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0025712
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0025712
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic; Pulmonary
Intervention: Hematologic; Ophthalmologic
Rationale: In Hereditary angioedema, individuals may have angioedema episodes that can be triggered by factors such as stress, oral contraceptives, ACE inhibitors, and angiotensin II receptor blockers, and medical management (eg, with tranexamic acid, icatibant) may be beneficial; In Plasminogen deficiency, medical treatment (eg, with hyaluronidase-containing eyedrops, topical corticosteroids, heparin, FFP, immunosuppression, and lysine-conjugated plasminogen) has been described as variably beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PLG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000301.5. 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 | 8 | 115 | 2 | 125 | ||
| missense | 6 | 3 | 289 | 22 | 4 | 324 |
| nonsense | 8 | 3 | 2 | 13 | ||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 1 | 7 | 2 | 10 | ||
| Total | 16 | 16 | 301 | 137 | 6 | 476 |
Highest pathogenic variant AF is 0.0049769804
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000292.1 | 19 | MANE Select | |
| Ensembl | ENSP00000308938.9 | 19 | MANE Select | |
| RefSeq | NP_001161810.1 | 4 | Standard | |
| Ensembl | ENSP00000516619.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
- Staphylococcus aureus infection - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Aminocaproic Acid Action Pathway
Biological Process
- platelet degranulation
- proteolysis
- blood coagulation
- negative regulation of cell population proliferation
- negative regulation of cell-substrate adhesion
Molecular Function
- endopeptidase activity
- serine-type endopeptidase activity
- signaling receptor binding
- protein binding
- serine-type peptidase activity
Cellular Component
- extracellular region
- extracellular space
- plasma membrane
- cell surface
- platelet alpha granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000308192
- Coding exons
- 19
- Length
- 51078
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125748
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.213 | 434 | 447 | 0.972 | 0.0000245 | 5290 |
| Missense (PolyPhen) | 115 | 172.25 | 0.66763 | 1991 | ||
| Synonymous | -0.933 | 182 | 167 | 1.09 | 0.0000101 | 1525 |
| Loss of Function | 4.57 | 13 | 46.7 | 0.279 | 0.00000238 | 544 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. {ECO:0000269|PubMed:14699093}.;
- Disease
- DISEASE: Plasminogen deficiency (PLGD) [MIM:217090]: A disorder characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. {ECO:0000269|PubMed:10233898, ECO:0000269|PubMed:1427790, ECO:0000269|PubMed:1986355, ECO:0000269|PubMed:6216475, ECO:0000269|PubMed:6238949, ECO:0000269|PubMed:8392398, ECO:0000269|PubMed:9242524, ECO:0000269|PubMed:9858247}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.774
Intolerance Scores
- LoFtool
- 0.211
- RVIS EVS
- 0.63
- RVIS percentile EVS
- 83.57
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 |