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S. Rashid, David Curtis, R. Garuti, Norma Anderson, Y. Bashmakov, Y. Ho, R. Hammer, Y. Moon, J. Horton (2005)
Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.Proceedings of the National Academy of Sciences of the United States of America, 102 15
M. Brown, J. Goldstein (1986)
A receptor-mediated pathway for cholesterol homeostasis.Science, 232 4746
Increased secretion of triglyceride - rich lipoproteins by transgenic mice expressing human D 374 Y PCSK 9 under physiological genetic control
M. McNutt, Thomas Lagace, J. Horton (2007)
Catalytic Activity Is Not Required for Secreted PCSK9 to Reduce Low Density Lipoprotein Receptors in HepG2 Cells*Journal of Biological Chemistry, 282
T. Innerarity, R. Mahley, K. Weisgraber, T. Bersot, R. Krauss, G. Vega, S. Grundy, Walter Friedl, J. Davignon, Brian McCarthy (1990)
Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia.Journal of lipid research, 31 8
O. Loubser, A. Marais, Maritha Kotze2, N. Godenir, Rochelle Thiart2, Charlotte Scholtz2, J Villiers2, Renate Hillermann2, J. Firth, H. Weich, F. Maritz, Sheena Jones2, D. Westhuyzen (1999)
Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestryClinical Genetics, 55
C. Betard, A. Kessling, M. Roy, Ann Chamberland, S. Lussier‐Cacan, J. Davignon (1992)
Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French CanadiansHuman Genetics, 88
C. Arambepola, A. Farmer, R. Perera, H. Neil, H. Neil (2007)
Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.Atherosclerosis, 195 2
D. Marks, M. Thorogood, S. Neil, S. Humphries, H. Neil (2006)
Cascade screening for familial hypercholesterolaemia: implications of a pilot study for national screening programmesJournal of Medical Screening, 13
D. Cunningham, D. Danley, K. Geoghegan, M. Griffor, J. Hawkins, T. Subashi, A. Varghese, M. Ammirati, J. Culp, L. Hoth, M. Mansour, Katherine McGrath, A. Seddon, S. Shenolikar, K. Stutzman-Engwall, Laurie Warren, Donghui Xia, X. Qiu (2007)
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemiaNature Structural &Molecular Biology, 14
Xi‐Ming Sun, E. Eden, I. Tosi, C. Neuwirth, D. Wile, R. Naoumova, A. Soutar (2005)
Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.Human molecular genetics, 14 9
J. Hoeg, I. Feuerstein, E. Tucker (1994)
Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia.Arteriosclerosis and thrombosis : a journal of vascular biology, 14 7
J. Horton, Jonathan Cohen, H. Hobbs (2009)
PCSK9: a convertase that coordinates LDL catabolism Published, JLR Papers in Press, November 19, 2008.Journal of Lipid Research, 50
E. Eden, Xi‐Ming Sun, D. Patel, A. Soutar (2007)
Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia.Human molecular genetics, 16 22
Eden (2002)
Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1J. Clin. Invest., 110
M. Abifadel, M. Varret, J. Rabès, D. Allard, K. Ouguerram, M. Devillers, C. Cruaud, S. Benjannet, L. Wickham, D. Erlich, A. Derré, Ludovic Villéger, M. Farnier, I. Beucler, E. Bruckert, J. Chambaz, B. Chanu, J. Lecerf, G. Luc, P. Moulin, J. Weissenbach, Annick Prat, M. Krempf, C. Junien, N. Seidah, C. Boileau (2003)
Mutations in PCSK9 cause autosomal dominant hypercholesterolemiaNature Genetics, 34
B. Herbert, D. Patel, S. Waddington, E. Eden, A. McAleenan, Xi‐Ming Sun, A. Soutar (2010)
Increased Secretion of Lipoproteins in Transgenic Mice Expressing Human D374Y PCSK9 Under Physiological Genetic ControlArteriosclerosis, Thrombosis, and Vascular Biology, 30
M. Abifadel, J. Rabès, M. Devillers, A. Munnich, D. Erlich, C. Junien, M. Varret, C. Boileau (2009)
Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and diseaseHuman Mutation, 30
P. Labonté, Syntia Begley, C. Guévin, M. Asselin, N. Nassoury, G. Mayer, A. Prat, N. Seidah (2009)
PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expressionHepatology, 50
A. Neil, J. Cooper, J. Betteridge, N. Capps, I. Mcdowell, P. Durrington, M. Seed, S. Humphries (2008)
Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry studyEuropean Heart Journal, 29
R. Naoumova, I. Tosi, D. Patel, C. Neuwirth, S. Horswell, A. Marais, C. Heyningen, A. Soutar (2005)
Severe Hypercholesterolemia in Four British Families With the D374Y Mutation in the PCSK9 Gene: Long-Term Follow-Up and Treatment ResponseArteriosclerosis, Thrombosis, and Vascular Biology, 25
K. Maxwell, R. Soccio, E. Duncan, E. Sehayek, J. Breslow (2003)
Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mices⃞s⃞ The online version of this article (available at http://www.jlr.org) contains one supplemental table. Published, JLR Papers in Press, August 1, 2003. DOI 10.1194/jlr.M300203-JLR200Journal of Lipid Research, 44
Dennis Norman, Xi‐Ming Sun, M. Bourbon, B. Knight, R. Naoumova, A. Soutar (1999)
Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.The Journal of clinical investigation, 104 5
E. Eden, D. Patel, Xi‐Ming Sun, J. Burden, M. Themis, M. Edwards, P. Lee, C. Neuwirth, R. Naoumova, A. Soutar (2002)
Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.The Journal of clinical investigation, 110 11
A. Soutar, R. Naoumova (2007)
Mechanisms of Disease: genetic causes of familial hypercholesterolemiaNature Clinical Practice Cardiovascular Medicine, 4
I. Tosi, P. Toledo-Leiva, C. Neuwirth, R. Naoumova, A. Soutar (2007)
Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.Atherosclerosis, 194 1
A. Hooper, A. Marais, D. Tanyanyiwa, John Burnett (2006)
Abstract 340: The C679X Mutation in PCSK9 is Present and Lowers Blood Cholesterol in a Southern African PopulationCirculation, 114
E. Eden, R. Naoumova, J. Burden, M. McCarthy, A. Soutar (2001)
Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.American journal of human genetics, 68 3
A. Khachadurian (1964)
THE INHERITANCE OF ESSENTIAL FAMILIAL HYPERCHOLESTEROLEMIA.The American journal of medicine, 37
J. Horton, Nila Shah, J. Warrington, Norma Anderson, Sahng-Wook Park, Michael Brown, J. Goldstein (2003)
Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genesProceedings of the National Academy of Sciences of the United States of America, 100
S. Leigh, A. Foster, R. Whittall, C. Hubbart, S. Humphries (2008)
Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia DatabaseAnnals of Human Genetics, 72
A. J. Hooper, A. D. Marais, D. M. Tanyanyiwa, J. R. Burnett (2007)
The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population, 193
Zhenze Zhao, Y. Tuakli‐Wosornu, Thomas Lagace, L. Kinch, N. Grishin, J. Horton, Jonathan Cohen, H. Hobbs (2006)
Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.American journal of human genetics, 79 3
K. Maxwell, J. Breslow (2004)
Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.Proceedings of the National Academy of Sciences of the United States of America, 101 18
G. Dubuc, A. Chamberland, H. Wassef, J. Davignon, N. Seidah, L. Bernier, A. Prat (2004)
Statins Upregulate PCSK9, the Gene Encoding the Proprotein Convertase Neural Apoptosis-Regulated Convertase-1 Implicated in Familial HypercholesterolemiaArteriosclerosis, Thrombosis, and Vascular Biology, 24
J. Cohen, A. Pertsemlidis, I. Kotowski, R. Graham, C. Garcia, H. Hobbs (2005)
Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9Nature Genetics, 37
J. Versmissen, Daniëlla Oosterveer, M. Yazdanpanah, J. Defesche, D. Basart, A. Liem, J. Heeringa, J. Witteman, P. Lansberg, J. Kastelein, E. Sijbrands (2008)
Efficacy of statins in familial hypercholesterolaemia: a long term cohort studyThe BMJ, 337
Familial hypercholesterolaemia (FH) is a human inherited disorder of metabolism characterised by increased serum low‐density lipoprotein (LDL) cholesterol. It is caused by defects in the LDL‐receptor pathway that impair normal uptake and clearance of LDL by the liver. The commonest cause of FH is mutations in LDLR, the gene for the LDL receptor, but defects also occur in APOB that encodes its major protein ligand. More recently, defects in two other genes, LDLRAP1 and PCSK9, have been found in patients with FH and investigation of these has shed new light on the functioning and complexity of the LDL receptor pathway. Cells from patients with autosomal recessive hypercholesterolaemia (ARH) fail to internalise the LDL receptor because they carry two defective alleles of LDLRAP1, a gene that encodes a specific clathrin adaptor protein. PCSK9 encodes proprotein convertase subtilisin kexin type 9, a secreted protein that binds to the LDL receptor and promotes its degradation. Gain‐of function mutations in PCSK9 are autosomal dominant and cause hypercholesterolaemia because they increase the affinity of PCSK9 protein for the LDL receptor, whereas loss‐of‐function mutations reduce serum cholesterol because LDL‐receptor protein is exposed to reduced PCSK9‐mediated degradation. Thus, PCSK9 has become a new target for cholesterol‐lowering drug therapy. © 2010 IUBMB IUBMB Life, 62(2): 125–131, 2010
IUBMB Life – Wiley
Published: Jan 1, 2010
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