PLAU

protein-coding

plasminogen activator, urokinase

Gene summary

This gene encodes a secreted serine protease that converts plasminogen to plasmin. The encoded preproprotein is proteolytically processed to generate A and B polypeptide chains. These chains associate via a single disulfide bond to form the catalytically inactive high molecular weight urokinase-type plasminogen activator (HMW-uPA). HMW-uPA can be further processed into the catalytically active low molecular weight urokinase-type plasminogen activator (LMW-uPA). This low molecular weight form does not bind to the urokinase-type plasminogen activator receptor. Mutations in this gene may be associated with Quebec platelet disorder and late-onset Alzheimer's disease. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

MANE transcript

NM_002658.6

Inheritance

ClinVar variants

U:65B:38

Top phenotype

Quebec platelet disorder

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr10:73,909,177-73,917,496

External References & Databases

Ensembl (ENSG00000122861)

Transcript & Mutation Effects

hg38 • Region Span ~8.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Quebec platelet disorderSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011136

Submitter: Orphanet

Quebec platelet disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011136

Submitter: Ambry Genetics

Quebec platelet disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011136

Submitter: Labcorp Genetics (formerly Invitae)

Quebec platelet disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011136

Submitter: PanelApp Australia

Quebec platelet disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011136

Submitter: ClinGen

*PLAU* was first reported in relation to autosomal dominant Quebec Platelet Disorder (QPD) in 2010 (Paterson et al, PMID: 20007542), however, the disorder was originally described in 1984 as Factor V (Quebec) (Tracy et al, PMID: 6480825). Evidence supporting this gene-disease curation includes case-level data, segregation data, and experimental data. A tandem 77.9kb duplication on chromosome 10 that encompasses the PLAU gene is the only variant associated with QPD. Quebec Platelet disorder was originally found in two co-probands from a large family from the Canadian province of Quebec and has since been described in at least 3 dozen additional people who also have the tandem duplication. In 2004, it was determined that the original co-probands and additional 3 dozen people are all members of a single family (McKay et al, PMID: 15026313) limiting the genetic evidence that could be used in this curation. The gene-disease relationship is supported by its altered expression in platelets (PMID: 11435291) and the functional alteration observed in patient cells (PMID: 19029443). Further support is provided in a mouse model in which the human phenotype is partially recapitulated (PMID: 12689937). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence, specifically more probands, are needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Although this curation has less than 3 probands, the Hemostasis and Thrombosis GCEP upgraded the gene-disease curation to moderate due to the very large pedigree with more than 3 dozen affected family members. This gene-disease classification was originally approved by the ClinGen Hemostasis and Thrombosis Gene Curation Expert Panel on January 5, 2022 and re-evaluated on February 5, 2024. No new genetic or experimental evidence emerged subsequent to the original curation date, and as a result, the classification did not change.

Clinical Genomic Database (CGD)

Quebec platelet disorderAD

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Fibrinolytic inhibitors can be effective for treatment of bleeding disorder

Refs: 15026313; 18988861; 20007542

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLAU variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 77

Quebec platelet disorderTotal: 42

not providedTotal: 25

PLAU-related disorderTotal: 12

C10orf55-related disorderTotal: 2

Alzheimer disease type 1Total: 2

Hirschsprung disease, susceptibility to, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002658.6. 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			1 clinvar	14 clinvar	2 clinvar	17
missense			58 clinvar	16 clinvar	6 clinvar	80
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	65	30	8	103

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002658.6	RefSeq	NP_002649.2	10	MANE Select
ENST00000372764.4	Ensembl	ENSP00000361850.3	10	MANE Select
NM_001145031.3	RefSeq	NP_001138503.2	9	Standard
NM_001319191.2	RefSeq	NP_001306120.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Prostate cancer - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)
MicroRNAs in cancer - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)

Biological Process

response to hypoxia
proteolysis
chemotaxis
signal transduction
blood coagulation

Molecular Function

serine-type endopeptidase activity
protein binding

Cellular Component

extracellular region
extracellular space
plasma membrane
focal adhesion
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372764
Coding exons: 10
Length: 8321
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.664	227	257	0.883	0.0000149	2817
Missense (PolyPhen)		89	110.41	0.80612		1220
Synonymous	0.686	91	99.7	0.913	0.00000589	813
Loss of Function	2.11	13	24.2	0.537	0.00000120	269

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00055	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.;
Disease: DISEASE: Quebec platelet disorder (QPD) [MIM:601709]: An autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. {ECO:0000269|PubMed:20007542}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.903

Intolerance Scores

LoFtool: 0.248
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.950

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium