PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] - Gene

Summary

Official Symbol: PCSK9provided by HGNC
Official Full Name: proprotein convertase subtilisin/kexin type 9provided by HGNC
Primary source: HGNC:HGNC:20001
See related: Ensembl:ENSG00000169174 MIM:607786; AllianceGenome:HGNC:20001
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: FH3; PC9; FHCL3; NARC1; LDLCQ1; NARC-1; HCHOLA3
Summary: This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
Expression: Biased expression in lung (RPKM 5.3), liver (RPKM 3.3) and 9 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 1p32.3

Exon count:: 15

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	1	NC_000001.11 (55039548..55064852)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	1	NC_060925.1 (54913987..54945736)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	1	NC_000001.10 (55505221..55530525)

Chromosome 1 - NC_000001.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Direct Impact of PCSK9 on SMC Senescence and Apoptosis: A New Focus in Cardiovascular Diseases.
Title: Direct Impact of PCSK9 on SMC Senescence and Apoptosis: A New Focus in Cardiovascular Diseases.
Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9.
Title: Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9.
PCSK9 E670G polymorphism increases risk of coronary artery disease in a Chinese Han population.
Title: PCSK9 E670G polymorphism increases risk of coronary artery disease in a Chinese Han population.
Roles of PCSK9 in the Pathogenesis of Periodontal Disease.
Title: Roles of PCSK9 in the Pathogenesis of Periodontal Disease.
LncRNA CYTOR knockdown inhibits tumor development via regulating miR-503-5p/PCSK9 in lung adenocarcinoma.
Title: LncRNA CYTOR knockdown inhibits tumor development via regulating miR-503-5p/PCSK9 in lung adenocarcinoma.
PCSK9 gene variations in the clinical setting of premature cardiovascular disease: A critical appraisal.
Title: PCSK9 gene variations in the clinical setting of premature cardiovascular disease: A critical appraisal.
Contrasting effects of intracellular and extracellular human PCSK9 on inflammation, lipid alteration and cell death.
Title: Contrasting effects of intracellular and extracellular human PCSK9 on inflammation, lipid alteration and cell death.
Association between Apo B, LDL-R and PCSK9 gene polymorphisms with coronary artery diseases in Egyptians.
Title: Association between Apo B, LDL-R and PCSK9 gene polymorphisms with coronary artery diseases in Egyptians.
Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C.
Title: Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C.
Methylation status of LDLR, PCSK9 and LDLRAP1 is associated with cardiovascular events in familial hypercholesterolemia.
Title: Methylation status of LDLR, PCSK9 and LDLRAP1 is associated with cardiovascular events in familial hypercholesterolemia.

Submit: New GeneRIF Correction See all GeneRIFs (704)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Professional guidelines

Description
Professional guideline ACMG 2013 The ACMG recommends that laboratories performing clinical sequencing seek and report mutations in PCSK9 that are pathogenic or expected to be pathogenic. GuidelinePubMed

Associated conditions

Description	Tests
Familial hypercholesterolemia MedGen: C0020445 GeneReviews: Familial Hypercholesterolemia	not available
Hypercholesterolemia, autosomal dominant, 3 MedGen: C1863551 OMIM: 603776 GeneReviews: Familial Hypercholesterolemia	not available

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2015-12-17) ClinGen Genome Curation Page Haploinsufficency Dosage sensitivity unlikely (Last evaluated 2015-12-17) ClinGen Genome Curation PagePubMed

EBI GWAS Catalog

Description
A genome-wide association study identifies susceptibility loci for Wilms tumor. EBI GWAS Catalog EBI GWAS CatalogPubMed
Biological, clinical and population relevance of 95 loci for blood lipids. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common variants at 30 loci contribute to polygenic dyslipidemia. EBI GWAS Catalog EBI GWAS CatalogPubMed
Discovery and refinement of loci associated with lipid levels. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic variants influencing circulating lipid levels and risk of coronary artery disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies multiple loci influencing human serum metabolite levels. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations. EBI GWAS Catalog EBI GWAS CatalogPubMed
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Newly identified loci that influence lipid concentrations and risk of coronary artery disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH18483 (e-PCR)
- UniSTS:57345

D1S2892 (e-PCR)
- UniSTS:33591

PCSK9_1729 (e-PCR)
- UniSTS:277570

D1S2722 (e-PCR), detects polymorphism
- UniSTS:22405

RH65068 (e-PCR)
- UniSTS:219

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables RNA binding	HDA more info	PubMed
enables apolipoprotein binding	ISS Inferred from Sequence or Structural Similarity more info
enables apolipoprotein receptor binding	IDA Inferred from Direct Assay more info	PubMed
enables low-density lipoprotein particle binding	ISS Inferred from Sequence or Structural Similarity more info
enables low-density lipoprotein particle receptor binding	IDA Inferred from Direct Assay more info	PubMed
enables low-density lipoprotein particle receptor binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables serine-type endopeptidase activity	IBA Inferred from Biological aspect of Ancestor more info
enables serine-type endopeptidase activity	IDA Inferred from Direct Assay more info	PubMed
enables signaling receptor inhibitor activity	IDA Inferred from Direct Assay more info	PubMed
enables sodium channel inhibitor activity	IDA Inferred from Direct Assay more info	PubMed
enables very-low-density lipoprotein particle binding	ISS Inferred from Sequence or Structural Similarity more info
enables very-low-density lipoprotein particle receptor binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in cellular response to insulin stimulus	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in cellular response to starvation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in cholesterol homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cholesterol metabolic process	IEA Inferred from Electronic Annotation more info
involved_in kidney development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in lipoprotein metabolic process	IEA Inferred from Electronic Annotation more info
involved_in liver development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in low-density lipoprotein particle receptor catabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in lysosomal transport	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of low-density lipoprotein particle clearance	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of low-density lipoprotein particle receptor binding	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of low-density lipoprotein receptor activity	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of receptor internalization	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of receptor recycling	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of receptor-mediated endocytosis involved in cholesterol transport	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of sodium ion transmembrane transporter activity	IDA Inferred from Direct Assay more info	PubMed
involved_in neurogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in neuron differentiation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in phospholipid metabolic process	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of low-density lipoprotein particle receptor catabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of neuron apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of receptor internalization	IDA Inferred from Direct Assay more info	PubMed
involved_in protein autoprocessing	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of neuron apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of signaling receptor activity	IDA Inferred from Direct Assay more info	PubMed
involved_in triglyceride metabolic process	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in COPII-coated ER to Golgi transport vesicle	IEA Inferred from Electronic Annotation more info
located_in Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
part_of PCSK9-AnxA2 complex	IDA Inferred from Direct Assay more info	PubMed
part_of PCSK9-AnxA2 complex	IPI Inferred from Physical Interaction more info	PubMed
part_of PCSK9-LDLR complex	IDA Inferred from Direct Assay more info	PubMed
located_in cell surface	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in early endosome	IDA Inferred from Direct Assay more info	PubMed
located_in endolysosome membrane	TAS Traceable Author Statement more info
located_in endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
located_in endoplasmic reticulum lumen	TAS Traceable Author Statement more info
located_in extracellular region	TAS Traceable Author Statement more info
is_active_in extracellular space	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular space	IDA Inferred from Direct Assay more info	PubMed
located_in extrinsic component of external side of plasma membrane	IC Inferred by Curator more info	PubMed
located_in late endosome	IDA Inferred from Direct Assay more info	PubMed
located_in lysosomal membrane	TAS Traceable Author Statement more info
located_in lysosome	IDA Inferred from Direct Assay more info	PubMed
located_in perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: proprotein convertase subtilisin/kexin type 9

Names: convertase subtilisin/kexin type 9 preproprotein; neural apoptosis regulated convertase 1; subtilisin/kexin-like protease PC9

NP_001394169.1

EC 3.4.21.-

NP_001394170.1

EC 3.4.21.-

NP_001394171.1

EC 3.4.21.-

NP_001394172.1

EC 3.4.21.-

NP_001394173.1

EC 3.4.21.-

NP_001394174.1

EC 3.4.21.-

NP_001394175.1

EC 3.4.21.-

NP_001394176.1

EC 3.4.21.-

NP_777596.2

EC 3.4.21.-

XP_054191774.1

EC 3.4.21.-

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_009061.1 RefSeqGene

Range

4930..30307

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_275

mRNA and Protein(s)

NM_001407240.1 → NP_001394169.1 proprotein convertase subtilisin/kexin type 9 isoform 2 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

UniProtKB/TrEMBL

A0AAQ5BGX4

Related

ENSP00000519088.1, ENST00000713786.1
NM_001407241.1 → NP_001394170.1 proprotein convertase subtilisin/kexin type 9 isoform 3 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_001407242.1 → NP_001394171.1 proprotein convertase subtilisin/kexin type 9 isoform 4 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_001407243.1 → NP_001394172.1 proprotein convertase subtilisin/kexin type 9 isoform 5 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_001407244.1 → NP_001394173.1 proprotein convertase subtilisin/kexin type 9 isoform 6 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_001407245.1 → NP_001394174.1 proprotein convertase subtilisin/kexin type 9 isoform 7 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_001407246.1 → NP_001394175.1 proprotein convertase subtilisin/kexin type 9 isoform 8

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

UniProtKB/TrEMBL

A0A669KBG0

Related

ENSP00000501257.1, ENST00000673903.1
NM_001407247.1 → NP_001394176.1 proprotein convertase subtilisin/kexin type 9 isoform 9 preproprotein

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NM_174936.4 → NP_777596.2 proprotein convertase subtilisin/kexin type 9 isoform 1 preproprotein

See identical proteins and their annotated locations for NP_777596.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the functional protein.

Source sequence(s)

AC091609, AL589790, BC042095, DA738424, EF692496

Consensus CDS

CCDS603.1

UniProtKB/Swiss-Prot

A8T640, C0JYY9, Q5PSM5, Q5SZQ2, Q8NBP7

UniProtKB/TrEMBL

A0AA34QVH0

Related

ENSP00000303208.5, ENST00000302118.5

Conserved Domains (3) summary

cd04077
Location:156 → 421

Peptidases_S8_PCSK9_ProteinaseK_like; Peptidase S8 family domain in ProteinaseK-like proteins

pfam00082
Location:180 → 422

Peptidase_S8; Subtilase family

pfam05922
Location:77 → 149

Inhibitor_I9; Peptidase inhibitor I9

RNA

NR_110451.3 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NR_176318.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

Related

ENST00000713785.1
NR_176319.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

Related

ENST00000713787.1
NR_176320.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

Related

ENST00000673913.2
NR_176321.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NR_176322.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NR_176323.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790
NR_176324.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC091609, AL589790

Related

ENST00000673726.2