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Gene Review

PCSK9  -  proprotein convertase subtilisin/kexin type 9

Homo sapiens

Synonyms: FH3, HCHOLA3, LDLCQ1, NARC-1, NARC1, ...
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Disease relevance of PCSK9


Psychiatry related information on PCSK9


High impact information on PCSK9


Chemical compound and disease context of PCSK9


Biological context of PCSK9

  • 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 [8].
  • To understand the physiological role of PCSK9, we overexpressed human PCSK9 in mouse and cellular models as well as attenuated the endogenous expression of PCSK9 in HuH7 hepatoma cells using RNA interference [10].
  • In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded [9].
  • Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype [11].
  • CONCLUSIONS: These results showed that the effect of the S127R mutation of PCSK9 on plasma cholesterol homeostasis is mainly related to an overproduction of apolipoprotein B100 [12].

Anatomical context of PCSK9


Associations of PCSK9 with chemical compounds

  • A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol [8].
  • Two independent microarray studies support a role for PCSK9 in sterol metabolism and adenoviral-mediated over-expression of PCSK9 in mouse liver depletes hepatic LDL-receptor protein, but the mechanism by which dominant mutations cause human FH is unclear [2].
  • METHODS AND RESULTS: In vivo kinetics of apolipoprotein B100-containing lipoproteins using a 14-hour primed constant infusion of [2H3] leucine was conducted in 2 subjects carrying the mutation S127R in PCSK9, controls subjects, and FH subjects with known mutations on the low-density lipoprotein (LDL) receptor gene (LDL-R) [12].
  • By cueing into the genomic basis for low serum LDL cholesterol levels, much work has been done to advance the importance of the serine protease PCSK9, which modulates LDL receptor function [13].
  • The PCSK9-induced degradation of the LDLR was not affected by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases [16].
  • This study demonstrates a more general effect of PCSK9 on the degradation of the LDLR family that emphasizes its major role in cholesterol and lipid homeostasis as well as brain development [17].
  • The authors' findings suggest that evolutionary dynamics may underlie the 'gain-of-function' mutations in PCSK9 that are associated with higher LDL cholesterol levels [18].

Physical interactions of PCSK9

  • LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients [19].
  • Structure-function analyses demonstrated that the C-terminal cysteine-histidine-rich domain of PCSK9 interacts specifically with the N-terminal repeat R1 of AnxA2 [20].

Enzymatic interactions of PCSK9

  • Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma [14].

Regulatory relationships of PCSK9

  • PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold) [12].
  • In FAO-1 cells PCSK9 expression is downregulated by cholesterol and 25-hydroxycholesterol and upregulated in the absence of sterols following the same pattern of expression as HMG-CoA reductase, synthase, and LDLR [21].

Other interactions of PCSK9


Analytical, diagnostic and therapeutic context of PCSK9


  1. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Abifadel, M., Varret, M., Rabès, J.P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derré, A., Villéger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J.M., Luc, G., Moulin, P., Weissenbach, J., Prat, A., Krempf, M., Junien, C., Seidah, N.G., Boileau, C. Nat. Genet. (2003) [Pubmed]
  2. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Sun, X.M., Eden, E.R., Tosi, I., Neuwirth, C.K., Wile, D., Naoumova, R.P., Soutar, A.K. Hum. Mol. Genet. (2005) [Pubmed]
  3. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. Cohen, J.C., Boerwinkle, E., Mosley, T.H., Hobbs, H.H. N. Engl. J. Med. (2006) [Pubmed]
  4. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Pisciotta, L., Oliva, C.P., Cefalù, A.B., Noto, D., Bellocchio, A., Fresa, R., Cantafora, A., Patel, D., Averna, M., Tarugi, P., Calandra, S., Bertolini, S. Atherosclerosis (2006) [Pubmed]
  5. Unravelling the functional significance of PCSK9. Lambert, G. Curr. Opin. Lipidol. (2007) [Pubmed]
  6. No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients. Shibata, N., Ohnuma, T., Higashi, S., Higashi, M., Usui, C., Ohkubo, T., Watanabe, T., Kawashima, R., Kitajima, A., Ueki, A., Nagao, M., Arai, H. Psychiatr. Genet. (2005) [Pubmed]
  7. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Cohen, J., Pertsemlidis, A., Kotowski, I.K., Graham, R., Garcia, C.K., Hobbs, H.H. Nat. Genet. (2005) [Pubmed]
  8. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Kotowski, I.K., Pertsemlidis, A., Luke, A., Cooper, R.S., Vega, G.L., Cohen, J.C., Hobbs, H.H. Am. J. Hum. Genet. (2006) [Pubmed]
  9. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Leren, T.P. Clin. Genet. (2004) [Pubmed]
  10. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. Lalanne, F., Lambert, G., Amar, M.J., Chétiveaux, M., Zaïr, Y., Jarnoux, A.L., Ouguerram, K., Friburg, J., Seidah, N.G., Brewer, H.B., Krempf, M., Costet, P. J. Lipid Res. (2005) [Pubmed]
  11. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Soutar, A.K., Naoumova, R.P. Nature clinical practice. Cardiovascular medicine (2007) [Pubmed]
  12. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Ouguerram, K., Chetiveaux, M., Zair, Y., Costet, P., Abifadel, M., Varret, M., Boileau, C., Magot, T., Krempf, M. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  13. Genetic susceptibility to myocardial infarction and coronary artery disease. Topol, E.J., Smith, J., Plow, E.F., Wang, Q.K. Hum. Mol. Genet. (2006) [Pubmed]
  14. The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A: FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N.G. J. Biol. Chem. (2006) [Pubmed]
  15. Low-density lipoprotein receptor activity in Epstein-Barr virus-transformed lymphocytes from heterozygotes for the D374Y mutation in the PCSK9 gene. Holla, Ø.L., Cameron, J., Berge, K.E., Kulseth, M.A., Ranheim, T., Leren, T.P. Scand. J. Clin. Lab. Invest. (2006) [Pubmed]
  16. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Maxwell, K.N., Fisher, E.A., Breslow, J.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. Poirier, S., Mayer, G., Benjannet, S., Bergeron, E., Marcinkiewicz, J., Nassoury, N., Mayer, H., Nimpf, J., Prat, A., Seidah, N.G. J. Biol. Chem. (2008) [Pubmed]
  18. Molecular population genetics of PCSK9: a signature of recent positive selection. Ding, K., Kullo, I.J. Pharmacogenet. Genomics (2008) [Pubmed]
  19. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Naoumova, R.P., Tosi, I., Patel, D., Neuwirth, C., Horswell, S.D., Marais, A.D., van Heyningen, C., Soutar, A.K. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  20. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. Mayer, G., Poirier, S., Seidah, N.G. J. Biol. Chem. (2008) [Pubmed]
  21. Expression and localization of PCSK9 in rat hepatic cells. Grozdanov, P.N., Petkov, P.M., Karagyozov, L.K., Dabeva, M.D. Biochem. Cell Biol. (2006) [Pubmed]
  22. Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. Poirier, S., Prat, A., Marcinkiewicz, E., Paquin, J., Chitramuthu, B.P., Baranowski, D., Cadieux, B., Bennett, H.P., Seidah, N.G. J. Neurochem. (2006) [Pubmed]
  23. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. Humphries, S.E., Whittall, R.A., Hubbart, C.S., Maplebeck, S., Cooper, J.A., Soutar, A.K., Naoumova, R., Thompson, G.R., Seed, M., Durrington, P.N., Miller, J.P., Betteridge, D.J., Neil, H.A. J. Med. Genet. (2006) [Pubmed]
  24. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Rashid, S., Curtis, D.E., Garuti, R., Anderson, N.N., Bashmakov, Y., Ho, Y.K., Hammer, R.E., Moon, Y.A., Horton, J.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. Lagace, T.A., Curtis, D.E., Garuti, R., McNutt, M.C., Park, S.W., Prather, H.B., Anderson, N.N., Ho, Y.K., Hammer, R.E., Horton, J.D. J. Clin. Invest. (2006) [Pubmed]
  26. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. McNutt, M.C., Kwon, H.J., Chen, C., Chen, J.R., Horton, J.D., Lagace, T.A. J. Biol. Chem. (2009) [Pubmed]
  27. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Zhao, Z., Tuakli-Wosornu, Y., Lagace, T.A., Kinch, L., Grishin, N.V., Horton, J.D., Cohen, J.C., Hobbs, H.H. Am. J. Hum. Genet. (2006) [Pubmed]
  28. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Varret, M., Rabès, 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., Buzzi, J.C., Kostner, G.M., Bertolini, S., Pocovi, M., Rosa, A., Farnier, M., Martinez, M., Junien, C., Boileau, C. Am. J. Hum. Genet. (1999) [Pubmed]
  29. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Seidah, N.G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S.B., Stifani, S., Basak, A., Prat, A., Chretien, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  30. FH Afrikaner-3 LDL receptor mutation results in defective LDL receptors and causes a mild form of familial hypercholesterolemia. Graadt van Roggen, J.F., van der Westhuyzen, D.R., Coetzee, G.A., Marais, A.D., Steyn, K., Langenhoven, E., Kotze, M.J. Arterioscler. Thromb. Vasc. Biol. (1995) [Pubmed]
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