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The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits
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Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 2004; 65:419-422.
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Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 2005; 25:2654-2660.
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Sun XM, Eden ER, Tosi I, et al. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet 2005; 14:1161-1169.
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Timms KM, Wagner S, Samuels ME, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 2004; 114:349-353.
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Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 2005; 26:497.
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Pisciotta L, Oliva CP, Cefalu AB, et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 2006; 186:433-440.
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Shioji K, Mannami T, Kokubo Y, et al. Genetic variants in PCSK9 affect the cholesterol level in Japanese. J Hum Genet 2004; 49:109-114.
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13
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A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis
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Chen SN, Ballantyne CM, Gotto AM Jr, et al. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005; 45:1611-1619.
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The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women
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Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet 2006; 7:66.
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Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 2006; 78:410-422. This paper describes new missense mutations on PCSK9 associated with low plasma LDL levels in two large cohorts.
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Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 2006; 78:410-422. This paper describes new missense mutations on PCSK9 associated with low plasma LDL levels in two large cohorts.
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The c.43_44insCTG variation in PCSK9 is associated with low plasma LDL-cholesterol in a Caucasian population
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Yue P, Averna M, Lin X, Schonfeld G. The c.43_44insCTG variation in PCSK9 is associated with low plasma LDL-cholesterol in a Caucasian population. Hum Mutat 2006; 27:460-466.
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Yue, P.1
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Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9
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Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161-165.
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Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2006; Sep 19 [Epub ahead of print]. This study reported for the first time the dramatically low LDL cholesterol levels in a PCSK9 loss of function homozygous female.
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Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2006; Sep 19 [Epub ahead of print]. This study reported for the first time the dramatically low LDL cholesterol levels in a PCSK9 loss of function homozygous female.
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Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-523. This report demonstrates that PCSK9 is secreted in the plasma and that loss of function mutations prevent either synthesis, trafficking or secretion of the mature PCSK9 protein.
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Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-523. This report demonstrates that PCSK9 is secreted in the plasma and that loss of function mutations prevent either synthesis, trafficking or secretion of the mature PCSK9 protein.
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Fasano T, Cefalu AB, Di Leo E, et al. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol 2006; 27:677-681.
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Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 2006; 26:1094-1100.
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Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272. Another breakthrough in PCSK9 genetics linking mutations in PCSK9 not only with reduced LDL but also with dramatically reduced incidence of cardiovascular disease over a 15-year period.
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Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272. Another breakthrough in PCSK9 genetics linking mutations in PCSK9 not only with reduced LDL but also with dramatically reduced incidence of cardiovascular disease over a 15-year period.
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Topol EJ, Smith J, Plow EF, Wang QK. Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet 2006; 15 (Spec No 2):R117-R123.
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Horton JD, Shah NA, Warrington JA, et al.Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A 2003; 100:12027-12032.
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Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, thegene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454-1459.
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Costet P, Cariou B, Lambert G, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006; 281:6211-6218. The authors provide a thorough analysis of how PCSK9 gene expression is regulated at the transcriptionnal level by insulin and cloning of the proximal promoter of PCSK9.
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Costet P, Cariou B, Lambert G, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006; 281:6211-6218. The authors provide a thorough analysis of how PCSK9 gene expression is regulated at the transcriptionnal level by insulin and cloning of the proximal promoter of PCSK9.
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Lambert G, Jarnoux AL, Pineau T, et al. 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 2006; 147:4985-4995. This report establishes the first direct evidence for a role for PCSK9 in VLDL hepatic production through effects on the LDLr.
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Lambert G, Jarnoux AL, Pineau T, et al. 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 2006; 147:4985-4995. This report establishes the first direct evidence for a role for PCSK9 in VLDL hepatic production through effects on the LDLr.
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Lalanne F, Lambert G, Amar MJ, et al. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 2005; 46:1312-1319.
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Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a postendoplasmic reticulum compartment. Proc Natl Acad Sci U S A 2005; 102:2069-2074.
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Maxwell KN, Breslow JL. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol 2005; 16:167-172.
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Benjannet S, Rhainds D, Hamelin J, et al. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and posttranslational modifications. J Biol Chem 2006; 281:30561-30572. This study demonstrated that the mature PCSK9 form is degraded by two other proprotein convertases which result in its inactivation and that this phenomenon does not occur for at least two PCSK9 missense mutants, which explains the familial hypercholesterolemia phenotype of carriers.
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Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006; 116:2995-3005. This elegant study unravelled the molecular mechanisms by which PCSK9 alters LDLr expression. It clearly demonstrated that PCSK9 acts both intracellularly and as a secreted protein and that it requires the LDLr and the ARH adaptor protein to be internalized and subsequently enhance LDLr degradation, in vitro and in vivo.
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Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006; 116:2995-3005. This elegant study unravelled the molecular mechanisms by which PCSK9 alters LDLr expression. It clearly demonstrated that PCSK9 acts both intracellularly and as a secreted protein and that it requires the LDLr and the ARH adaptor protein to be internalized and subsequently enhance LDLr degradation, in vitro and in vivo.
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