Published online before print January 19, 2006, doi: 10.1161/01.ATV.0000204337.81286.1c
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Missense Mutations in the PCSK9 Gene Are Associated With Hypocholesterolemia and Possibly Increased Response to Statin Therapy
From the Medical Genetics Laboratory, Department of Medical Genetics (K.E.B. T.P.L.) and Lipid Clinic, Department of Medicine (L.O.), Rikshospitalet University Hospital, Oslo, Norway.
Correspondence to Trond P. Leren, Medical Genetics Laboratory. Department of Medical Genetics Rikshospitalet University Hospital, N-0027 Oslo, Norway. E-mail trond.leren{at}rikshospitalet.no
Objective— The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene encodes a proprotein convertase that causes degradation of cell surface low-density lipoprotein receptors (LDLRs). Mutations in the PCSK9 gene that disrupt the normal function of PCSK9 could therefore result in increased number of LDLRs and hypocholesterolemia. Also, the cholesterol-lowering effect of statins could be increased in subjects carrying mutations in the PCSK9 gene.
Methods and Results— We have screened 38 unrelated hypocholesterolemic subjects as well as 25 unrelated familial hypercholesterolemia (FH) heterozygotes who responded particularly well to statin therapy for mutations in the 12 exons of the PCSK9 gene by DNA sequencing. Six of the 38 (15.8%) hypocholesterolemic subjects were heterozygous for 1 of the 3 mutations R46L, G106R, or R237W in the PCSK9 gene. In the group of 25 FH heterozygotes who responded particularly well to statin therapy, 3 (8.8%) were heterozygous for mutations R46L or N157K in the PCSK9 gene. None of 441 hypercholesterolemic subjects without mutations in the LDLR gene or in the apolipoprotein B-100 gene possessed any of the 4 mutations.
Conclusion— The 4 missense mutations R46L, G106R, N157K, and R237W are associated with hypocholesterolemia and possibly increased response to statin therapy.
We have screened 38 unrelated hypocholesterolemic subjects and 25 unrelated FH heterozygotes, who responded particularly well to statin therapy, for mutations in the PCSK9 gene; 15.8% of the hypocholesterolemic subjects and 8.8% of FH heterozygotes with good a response to statins possessed a missense mutation in the PCSK9 gene.
Key Words: familial hypercholesterolemia • hypocholesterolemia • mutation • PCSK9 • statin
This article has been cited by other articles:
 |
|
 |
|
  A. S. Peterson, L. G. Fong, and S. G. Young Errata. PCSK9 function and physiology J. Lipid Res., July 1, 2008; 49(7): 1595 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pandit, D. Wisniewski, J. C. Santoro, S. Ha, V. Ramakrishnan, R. M. Cubbon, R. T. Cummings, S. D. Wright, C. P. Sparrow, A. Sitlani, et al. Functional analysis of sites within PCSK9 responsible for hypercholesterolemia J. Lipid Res., June 1, 2008; 49(6): 1333 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Peterson, L. G. Fong, and S. G. Young PCSK9 function and physiology J. Lipid Res., June 1, 2008; 49(6): 1152 - 1156. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kourimate, C. Le May, C. Langhi, A. L. Jarnoux, K. Ouguerram, Y. Zair, P. Nguyen, M. Krempf, B. Cariou, and P. Costet Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9 J. Biol. Chem., April 11, 2008; 283(15): 9666 - 9673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Careskey, R. A. Davis, W. E. Alborn, J. S. Troutt, G. Cao, and R. J. Konrad Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9 J. Lipid Res., February 1, 2008; 49(2): 394 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. E. Alborn, G. Cao, H. E. Careskey, Y.-W. Qian, D. R. Subramaniam, J. Davies, E. M. Conner, and R. J. Konrad Serum Proprotein Convertase Subtilisin Kexin Type 9 Is Correlated Directly with Serum LDL Cholesterol Clin. Chem., October 1, 2007; 53(10): 1814 - 1819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. N. Hampton, M. W. Knuth, J. Li, J. L. Harris, S. A. Lesley, and G. Spraggon The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain PNAS, September 11, 2007; 104(37): 14604 - 14609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Fisher, P. L. Surdo, S. Pandit, M. Mattu, J. C. Santoro, D. Wisniewski, R. T. Cummings, A. Calzetta, R. M. Cubbon, P. A. Fischer, et al. Effects of pH and Low Density Lipoprotein (LDL) on PCSK9-dependent LDL Receptor Regulation J. Biol. Chem., July 13, 2007; 282(28): 20502 - 20512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-W. Qian, R. J. Schmidt, Y. Zhang, S. Chu, A. Lin, H. Wang, X. Wang, T. P. Beyer, W. R. Bensch, W. Li, et al. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis J. Lipid Res., July 1, 2007; 48(7): 1488 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fasano, A. B. Cefalu, E. Di Leo, D. Noto, D. Pollaccia, L. Bocchi, V. Valenti, R. Bonardi, O. Guardamagna, M. Averna, 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., March 1, 2007; 27(3): 677 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Benjannet, D. Rhainds, J. Hamelin, N. Nassoury, and N. G. Seidah 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., October 13, 2006; 281(41): 30561 - 30572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lambert, A.-L. Jarnoux, T. Pineau, O. Pape, M. Chetiveaux, C. Laboisse, M. Krempf, and P. Costet 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, October 1, 2006; 147(10): 4985 - 4995. [Abstract] [Full Text] [PDF]
|
|