Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK9
SNOMEDCT: 441471003;
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38): 1:55,039,548-55,064,852 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.3 | {Low density lipoprotein cholesterol level QTL 1} | 603776 | Autosomal dominant | 3 |
| Hypercholesterolemia, familial, 3 | 603776 | Autosomal dominant | 3 |
PCSK9 is a serine protease that reduces both hepatic and extrahepatic low-density lipoprotein (LDL) receptor (LDLR; 606945) levels and increases plasma LDL cholesterol (Schmidt et al., 2008).
To identify the gene mutant in the form of autosomal dominant familial hypercholesterolemia (see 143890) that had been mapped to chromosome 1p32 (HCHOLA3; 603776), Abifadel et al. (2003) undertook positional cloning using the family in which linkage was originally identified (Varret et al., 1999) and 23 French families in which a causative mutation in LDLR (606945) or APOB (107730) had been excluded. The critical linkage region contained 41 genes, including the PCSK9 gene. Abifadel et al. (2003) found that the PCSK9 cDNA spans 3,617 basepairs and encodes a protein of 692 amino acids, known as NARC1. PCSK9 was expressed most abundantly in liver, small intestine, and kidney.
Kwon et al. (2008) stated that PCSK9 contains an N-terminal signal peptide, followed by a prodomain, a subtilisin-like catalytic domain, and a C-terminal domain. The prodomain serves as a chaperone for folding and as an inhibitor of catalytic activity. Autocatalysis between gln152 and ser153 separates the prodomain from the catalytic domain, but the prodomain remains bound, occluding the catalytic site. The C-terminal domain is predicted to mediate protein-protein interactions.
Benjannet et al. (2006) reported that PCSK9 is N-glycosylated at asn533 and that both the prosegment and the catalytic domain contain a sulfated tyrosine.
Abifadel et al. (2003) determined that the PCSK9 gene comprises 12 exons.
By genomic sequence analysis, Abifadel et al. (2003) mapped the PCSK9 gene to chromosome 1p32.
Crystal Structure
Kwon et al. (2008) determined the crystal structure of PCSK9 in complex with the first EGF-like repeat (EGF-A) of LDLR to 2.4-angstrom resolution. They found that the N-terminal region of EGF-A bound to the surface of PCSK9 that is formed primarily by residues 367 to 381; residues 153 to 155 in the catalytic domain also contribute to the interface. Arg194 and phe379 within the catalytic domain were critical for EGF-A binding, since arg194 formed a salt bridge with EGF-A, and phe379 made several hydrophobic contacts. Mutation of either residue decreased PCSK9 binding by greater than 90%.
Abifadel et al. (2003) stated that the PCSK9 gene encodes NARC1, a novel putative proprotein convertase belonging to the subtilase subfamily (Seidah et al., 2003). NARC1 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. Prosegment cleavage is necessary for NARC1 to exit from the endoplasmic reticulum. A related protein is the subtilisin/kexin isoenzyme-1/site-1 protease (603355), which has a key role in cholesterol homeostasis through processing the sterol regulatory element-binding proteins.
Maxwell et al. (2005) found that overexpression of mouse Pcsk9 in a human hepatoma cell line caused a decrease in whole-cell and cell-surface LDLR levels. Overexpression had no effect on LDLR synthesis, but caused a dramatic increase in the degradation of the mature receptor and a lesser increase in the degradation of the LDLR precursor. In contrast, overexpression of a catalytically inactive Pcsk9 mutant prevented the degradation of the mature LDLR, but precursor degradation remained elevated. Pcsk9-induced LDLR degradation was not altered by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases, but required transport out of the endoplasmic reticulum.
Benjannet et al. (2006) found that the mature secreted 60-kD PCSK9 protein could be further processed by membrane-bound furin (136950) and, to a lesser extent, soluble PC5/6A (PCSK5; 600488) into an approximately 53-kD form. Processing at the furin cleavage site led to disassociation of the inhibitory prosegment.
Kwon et al. (2008) stated that PCSK9 binds in a calcium-dependent manner to the EGF-A domain of the EGF-precursor homology domain of LDLR, but the catalytic domain of PCSK9 is not required for normal LDLR turnover. They found that deletion of the first 21 amino acids of the prodomain region of PCSK9 (called delta-53-PCSK9) increased the affinity of PCSK9 over 7-fold compared with full-length PCSK9. The affinity of both full-length PCSK9 and delta-53-PCSK9 increased about 3-fold when the pH was lowered from 7.0 to 6.0, suggesting that PCSK9 binds more avidly to LDLR in the lysosomal/endosomal compartment.
Schmidt et al. (2008) showed that recombinant human PCSK9, when intravenously injected in mice or expressed in mouse liver, reduced Ldlr levels in multiple extrahepatic tissues, including lung, adipose, and kidney, with more dramatic reduction in liver. Wildtype PCSK9 and a catalytically inactive PCSK9 mutant showed similar reductions in hepatic Ldlr levels, indicating that the catalytic activity of secreted PCSK9 is not necessary to reduce LDLR levels in vivo.
Familial Hypercholesterolemia 3, Autosomal Dominant
By sequencing the 12 exons of PCSK9 in a French family (HC92) with hypercholesterolemia (FHCL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, predicting a ser127-to-arg (S127R) amino acid change (607786.0001). They found the mutation in 12 affected family members and in 1 family member whose total cholesterol level was in the 90th percentile when compared with other French individuals matched by age and sex. Thus, the penetrance in the family was estimated at 0.94. The authors also found the same mutation in another affected French family. The S127R mutation is located between the primary and putative secondary zymogen processing sites of the NARC1 propeptide. In another affected French family, Abifadel et al. (2003) found another missense mutation in the PCSK9 gene (F216L; 607786.0002), which was located close to the active site at his226. The molecular mechanisms that underlie the dominance of the trait caused by these missense mutations was unclear. That only missense mutations had been identified favors a gain-of-function or dominant-negative mechanism.
By mutation screening of genes in the chromosome 1p32 region in patients with familial hypercholesterolemia from the Utah pedigree (K1173) studied by Haddad et al. (1999) and Hunt et al. (2000), Timms et al. (2004) identified a heterozygous missense mutation (D374Y; 607786.0003) in the PCSK9 gene.
Sun et al. (2005) identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (107730)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. Sun et al. (2005) suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers.
Low Density Lipoprotein cholesterol level Quantitative Trait Locus 1
In a 1,793-person cohort representing the general population of Japan, Shioji et al. (2004) directly sequenced the PCSK9 gene and identified 21 polymorphisms, 2 of which were significantly associated with lower levels of total cholesterol and low density lipoprotein (LDL) cholesterol (LDLCQ1; see 603776): a -161C-T transition in intron 1 and an ile474-to-val (I474V) change in exon 9.
As indicated, mutations in PCSK9 causing hypercholesterolemia are probably gain-of-function mutations; overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number (Maxwell and Breslow, 2004; Park et al., 2004). To test whether loss-of-function mutations in PCSK9 have the opposite effect, Cohen et al. (2005) sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL cholesterol and found 2 nonsense mutations: Y142X (607786.0004) and C679X (607786.0005). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (less than 0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol (LDLCQ1; see 603776). The data indicated that common sequence variations have large effects on plasma cholesterol levels in selected populations. The high frequency of these 2 ancient nonsense mutations in individuals of African ancestry suggested that positive selection pressure may have maintained these alleles in the population.
Selected missense mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia (e.g., 607786.0001), whereas nonsense mutations in the same gene are associated with low plasma levels of low density lipoprotein cholesterol (LDL-C) (e.g., 607786.0004). Kotowski et al. (2006) used DNA sequencing and chip-based oligonucleotide hybridization to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n = 3,543) who had the lowest (less than 5th percentile) and highest (more than 95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, R46L (607786.0006; rs11591147), L253F, and A443T were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5 to 30%). None of the low LDL-C variants was associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding was considered most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2 to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contributed to interindividual differences in LDL-C levels. These findings revealed that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and made it an attractive therapeutic target for LDL-C lowering.
Cohen et al. (2006) examined the effect of DNA sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. Of the 3,363 black subjects examined, 2.6% had nonsense mutations in PCSK9; these mutations were associated with a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of coronary heart disease (CHD), including myocardial infarction, fatal CHD, or coronary revascularization, over a 15-year period. Of the 9,524 white subjects examined, 3.2% had a sequence variation in PCSK9 that was associated with a 15% reduction in LDL cholesterol and a 47% reduction in the risk of CHD.
Zhao et al. (2006) showed that 4 severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wildtype PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the serum and identified the first known individual who had no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for 2 inactivating mutations in PCSK9 (607786.0007, 607786.0008) had a strikingly low plasma level of LDL cholesterol (14 mg/dL). The very low plasma level of LDL cholesterol and apparent good health of this individual demonstrates that PCSK9 plays a major role in determining plasma levels of LDL cholesterol and provides an attractive target for LDL-lowering therapy. Findings in this patient recapitulate those found in mice with no PCSK9, which show accelerated LDL clearance (Rashid et al., 2005). Evidence suggests that PCSK9 acts to limit the number of LDL receptors at the cell surface. Thus, the PCSK9 mutations associated with hypercholesterolemia are presumably gain-of-function mutations, whereas those reported by Zhao et al. (2006) are loss-of-function mutations.
Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs11591147 of PCSK9, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.
Mayne et al. (2007) examined the relationship between plasma PCSK9 levels and lipoprotein parameters in 182 normolipidemic individuals and found a correlation between plasma PCSK9 and total cholesterol, LDL cholesterol, and the total cholesterol/HDL cholesterol ratio in men but not in women. Analysis of the PCSK9 gene in 3 individuals with total and LDL cholesterol levels below the fifth percentile revealed compound heterozygosity for known PCSK9 mutations; analysis of family members of 1 proband showed that the ratio of plasma PCSK9/LDLC was increased in men, but not women, carrying loss of function PCSK9 variants. Mayne et al. (2007) suggested that there is a gender difference in PCSK9 regulation and function, with PCSK9 correlated to total and LDL cholesterol in men but not women.
Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified rs2479409 near the PCSK9 gene as implicated in LDL cholesterol concentrations with an effect size of +2.01 mg per deciliter and a P value of 2 x 10(-28).
Benjannet et al. (2006) found that the hypercholesterolemia-associated gain-of-function PCSK9 mutations R218S, F216L, and D374Y resulted in total or partial loss of processing of mature PCSK9 at the furin cleavage motif RFHR. In contrast, the hypocholesterolemia-associated loss-of-function PCSK9 mutations A443T and C679X resulted in abnormal subcellular localization and enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X).
To study the function of Pcsk9 in mice, Maxwell and Breslow (2004) used an adenovirus constitutively expressing murine Pcsk9 (Pcsk9-Ad). Pcsk9 overexpression in wildtype mice caused a 2-fold increase in plasma total cholesterol and a 5-fold increase in non-high density lipoprotein (HDL) cholesterol, with no increase in HDL cholesterol, as compared with mice infected with a control adenovirus. The increase in non-HDL cholesterol was shown to be due to an increase in low density lipoprotein (LDL) cholesterol. This effect appeared to depend on the LDL receptor (LDLR; 606945) because Ldlr knockout mice infected with Pcsk9-Ad showed no change in plasma cholesterol levels as compared with knockout mice infected with a control adenovirus. Furthermore, whereas overexpression of Pcsk9 had no effect on Ldlr mRNA levels, there was a near absence of Ldlr protein in animals overexpressing Pcsk9. These and other results indicated that overexpression of PCSK9 interferes with LDLR-mediated LDL cholesterol uptake. Because PCSK9 and LDLR are coordinately regulated by cholesterol, Maxwell and Breslow (2004) suggested that PCSK9 may be involved in a novel mechanism to modulate LDLR function by an alternative pathway than classic cholesterol inhibition of sterol regulatory element binding protein-mediated transcription.
Rashid et al. (2005) found that the livers of mice lacking Pcsk9 showed increased LDLR protein but not mRNA. Increased LDLR led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels. Administration of a statin-class drug to Pcsk9-null mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma.
Lambert et al. (2006) showed that upon dietary challenge, downregulation of Ldlr in mice is a key mechanism whereby Pcsk9 modulates hepatic production of Apob-containing lipoproteins. Overexpression of Pcsk9 in mice promoted hypercholesterolemia and massive hypertriglyceridemia following a 24-hour fast due to dramatically increased hepatic output of very low density lipoprotein (VLDL) and Apob, and both processes required Ldlr. Increased VLDL production was associated with a concomitant reduction of intrahepatic lipid stores and absence of Ppara (170998) downregulation. Experiments with a Ppara agonist confirmed that hepatic expression of Pcsk9 was negatively regulated by Ppara.
In 2 French families with autosomal dominant hypercholesterolemia-3 (FCHL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, resulting in a ser127-to-arg (S127R) substitution.
Kwon et al. (2008) stated that PCSK9 processing and secretion were reduced in PCSK9 containing the S127R mutation, but the affinity of PCSK9 for LDLR was only modestly affected.
Ouguerram et al. (2004) found that the S127R mutation in 2 related individuals with hypercholesterolemia was associated with increased production of APOB (3-fold) related to overproduction of VLDL (3-fold), intermediate density lipoprotein (IDL) (3-fold), and LDL (5-fold) compared with controls. The 2 individuals also showed a decrease in VLDL and IDL conversion (10 to 30% of controls), and their LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls.
In the proband of a family with autosomal dominant hypercholesterolemia-3 (FHCL3; 603776) who died from myocardial infarction at 49 years of age, Abifadel et al. (2003) identified an 890T-C transition in exon 4 of the PCSK9 gene, resulting in a phe216-to-leu (F216L) substitution.
Kwon et al. (2008) stated that phe216 is located within a disordered loop in PCSK9 and that the F216L mutation reduces proteolytic processing of PCSK9 after arg218.
In a large Utah pedigree (K1173) segregating hypercholesterolemia (FHCL3; 603776), originally described by Haddad et al. (1999), Hunt et al. (2000) found linkage of the disorder to chromosome 1p32. By mutation screening of genes in this region, Timms et al. (2004) identified a G-to-T transversion in the PCSK9 gene, resulting in an asp374-to-tyr (D374Y) substitution.
Sun et al. (2005) identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (107730)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. Sun et al. (2005) suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers.
Kwon et al. (2008) found that the D374Y mutation increased the affinity of mutant PCSK9 for LDLR compared with wildtype PCSK9.
In 3 of 64 African American subjects with low plasma levels of low density lipoprotein cholesterol (LDLCQ1; see 603776), Cohen et al. (2005) identified a 426C-G transversion in exon 3 of the PCSK9 gene, resulting in a tyr142-to-ter mutation (Y142X). This mutation was predicted to delete the last four-fifths of the protein. The authors hypothesized that the Y142X mutation would induce nonsense-mediated mRNA decay. This is one of the sequence variations found by Cohen et al. (2006) to be associated with protection against coronary heart disease in black participants in a longitudinal study.
In 4 of 64 African American subjects with low plasma levels of LDL cholesterol (LDLCQ1; see 603776), Cohen et al. (2005) found a 2037C-A transversion in the PCSK9 gene that was predicted to truncate the protein by 14 amino acids (cys679 to ter; C679X). Among 549 Nigerians from a Yoruba-speaking rural community, they found a frequency of the 2037A allele of 1.4%, which was similar to the frequencies observed in 2 African American populations. This is one of the sequence variations found by Cohen et al. (2006) to be associated with protection against coronary heart disease in black participants in a longitudinal study.
Cohen et al. (2006) found that the arg46-to-leu (R46L) substitution (rs11591147) in white subjects in a longitudinal study was associated with significant reduction in plasma levels of total cholesterol (9%) and LDL cholesterol (15%) (see 603776). Cohen et al. (2006) found that persons who were heterozygous or homozygous for PCSK9(46L) had a 47% reduction in the rate of coronary events (6.3% vs 11.8%).
Kathiresan (2008) reported a significant association between the R46L variant and decreased risk of early-onset myocardial infarction in a study of 1,454 patients from 5 different study sites (metaanalysis odds ratio of 0.40; p = 2.0 x 10(-5)). The R46L allele frequency in 1,617 controls was 2.4%.
Zhao et al. (2006) identified the first known individual with no immunodetectable circulating PCSK9. This healthy, fertile college graduate was found to be a compound heterozygote for 2 inactivating mutations in PCSK9, a tyr142-to-stop substitution on the maternal allele (Y142X) that disrupted synthesis of the protein, and a 3-bp deletion on the paternal allele (607786.0008). She had a strikingly low plasma level of LDL cholesterol (14 mg/dL) (see 603776).
A patient with no immunodetectable circulating PCSK9 reported by Zhao et al. (2006) carried a 3-bp deletion (290_292delGCC) on the paternal allele of her PCSK9 gene that removed an arginine at codon 97 (see 603776). Expression of the mutant protein in HEK293 cells demonstrated that the mutation prevents autocatalytic cleavage and secretion of PCSK9. The maternal allele carried a premature termination mutation (607786.0007).
Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genet. 34: 154-156, 2003. [PubMed: 12730697] [Full Text: https://doi.org/10.1038/ng1161]
Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J. Biol. Chem. 281: 30561-30572, 2006. [PubMed: 16912035] [Full Text: https://doi.org/10.1074/jbc.M606495200]
Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New Eng. J. Med. 354: 1264-1272, 2006. [PubMed: 16554528] [Full Text: https://doi.org/10.1056/NEJMoa054013]
Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005. [PubMed: 15654334] [Full Text: https://doi.org/10.1038/ng1509]
Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N. Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred. J. Lipid Res. 40: 1113-1122, 1999. [PubMed: 10357843]
Hunt, S. C., Hopkins, P. N., Bulka, K., McDermott, M. T., Thorne, T. L., Wardell, B. B., Bowen, B. R., Ballinger, D. G., Skolnick, M. H., Samuels, M. E. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler. Thromb. Vasc. Biol. 20: 1089-1093, 2000. [PubMed: 10764678] [Full Text: https://doi.org/10.1161/01.atv.20.4.1089]
Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. Polymorphisms associated with cholesterol and risk of cardiovascular events. New Eng. J. Med. 358: 1240-1249, 2008. [PubMed: 18354102] [Full Text: https://doi.org/10.1056/NEJMoa0706728]
Kathiresan, S. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. (Letter) New Eng. J. Med. 358: 2299-2300, 2008. [PubMed: 18499582] [Full Text: https://doi.org/10.1056/NEJMc0707445]
Kotowski, I. K., Pertsemlidis, A., Luke, A., Cooper, R. S., Vega, G. L., Cohen, J. C., Hobbs, H. H. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78: 410-422, 2006. [PubMed: 16465619] [Full Text: https://doi.org/10.1086/500615]
Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. Molecular basis for LDL receptor recognition by PCSK9. Proc. Nat. Acad. Sci. 105: 1820-1825, 2008. [PubMed: 18250299] [Full Text: https://doi.org/10.1073/pnas.0712064105]
Lambert, G., Jarnoux, A.-L., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., Costet, P. Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor. Endocrinology 147: 4985-4995, 2006. [PubMed: 16794006] [Full Text: https://doi.org/10.1210/en.2006-0098]
Maxwell, K. N., Breslow, J. L. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Nat. Acad. Sci. 101: 7100-7105, 2004. [PubMed: 15118091] [Full Text: https://doi.org/10.1073/pnas.0402133101]
Maxwell, K. N., Fisher, E. A., Breslow, J. L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Nat. Acad. Sci. 102: 2069-2074, 2005. [PubMed: 15677715] [Full Text: https://doi.org/10.1073/pnas.0409736102]
Mayne, J., Raymond, A., Chaplin, A., Cousins, M., Kaefer, N., Gyamera-Acheampong, C., Seidah, N. G., Mbikay, M., Chretien, M., Ooi, T. C. Plasma PCSK9 levels correlate with cholesterol in men but not in women. Biochem. Biophys. Res. Commun. 361: 451-456, 2007. [PubMed: 17645871] [Full Text: https://doi.org/10.1016/j.bbrc.2007.07.029]
Ouguerram, K., Chetiveaux, M., Zair, Y., Costet, P., Abifadel, M., Varret, M., Boileau, C., Magot, T., Krempf, M. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler. Thromb. Vasc. Biol. 24: 1448-1453, 2004. [PubMed: 15166014] [Full Text: https://doi.org/10.1161/01.ATV.0000133684.77013.88]
Park, S. W., Moon, Y.-A., Horton, J. D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279: 50630-50638, 2004. [PubMed: 15385538] [Full Text: https://doi.org/10.1074/jbc.M410077200]
Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., Horton, J. D. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Nat. Acad. Sci. 102: 5374-5379, 2005. [PubMed: 15805190] [Full Text: https://doi.org/10.1073/pnas.0501652102]
Schmidt, R. J., Beyer, T. P., Bensch, W. R., Qian, Y.-W., Lin, A., Kowala, M., Alborn, W. E., Konrad, R. J., Cao, G. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun. 370: 634-640, 2008. [PubMed: 18406350] [Full Text: https://doi.org/10.1016/j.bbrc.2008.04.004]
Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Nat. Acad. Sci. 100: 928-933, 2003. [PubMed: 12552133] [Full Text: https://doi.org/10.1073/pnas.0335507100]
Shioji, K., Mannami, T., Kokubo, Y., Inamoto, N., Takagi, S., Goto, Y., Nonogi, H., Iwai, N. Genetic variants in PCSK9 affect the cholesterol level in Japanese. J. Hum. Genet. 49: 109-114, 2004. [PubMed: 14727156] [Full Text: https://doi.org/10.1007/s10038-003-0114-3]
Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum. Molec. Genet. 14: 1161-1169, 2005. [PubMed: 15772090] [Full Text: https://doi.org/10.1093/hmg/ddi128]
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., Johansen, C. T., Fouchier, S. W., and 197 others. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707-713, 2010. [PubMed: 20686565] [Full Text: https://doi.org/10.1038/nature09270]
Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., Shattuck, D. M. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum. Genet. 114: 349-353, 2004. [PubMed: 14727179] [Full Text: https://doi.org/10.1007/s00439-003-1071-9]
Varret, M., Rabes, J.-P., Saint-Jore, B., Cenarro, A., Marinoni, J.-C., Civeira, F., Devillers, M., Krempf, M., Coulon, M., Thiart, R., Kotze, M. J., Schmidt, H., and 9 others. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am. J. Hum. Genet. 64: 1378-1387, 1999. [PubMed: 10205269] [Full Text: https://doi.org/10.1086/302370]
Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79: 514-523, 2006. [PubMed: 16909389] [Full Text: https://doi.org/10.1086/507488]