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Human Molecular Genetics Advance Access published online on March 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl077
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 23, 2005
Revised March 14, 2006
Accepted March 22, 2006

Article

Effect of mutations in the PCSK9 gene on the cell surface LDL receptors

Jamie Cameron 1, Øystein L. Holla 1, Trine Ranheim 1, Mari Ann Kulseth 1, Knut Erik Berge M.D. PhD 2 *, and Trond P. Leren 1

1 Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway
2 Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, N-0027 Oslo, Norway

* To whom correspondence should be addressed.
Knut Erik Berge, E-mail: knut.erik.berge{at}rikshospitalet.no


  Abstract

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is involved in the post-transcriptional regulation of the low density lipoprotein receptors (LDLR). Mutations in the PCSK9 gene have been associated both with hypocholesterolemia and hypercholesterolemia through "loss of function" and "gain of function" mechanisms, respectively. We have studied the effect of the four "loss of function" mutations R46L, G106R, N157K and R237W and the two "gain of function" mutations S127R and D374Y on the autocatalytic activity of PCSK9, as well as on the amount of the cell surface LDLR and internalization of LDL in transiently transfected HepG2 cells. The two groups of mutations did not differ with respect to autocatalytic activity of PCSK9, but they did differ with respect to the amount of cell surface LDLR and internalization of LDL. The four "loss of function" mutations had a 16% increased level of cell surface LDLR and a 35% increased level of internalization of LDL as compared to WT-PCSK9. The two "gain of function" mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared to WT-PCSK9. Our studies have also shown that transfer of media from transiently transfected HepG2 cells to untransfected HepG2 cells, reduces the amount of cell surface LDLR and internalization of LDL in the untransfected cells within 20 minutes of media transfer. Thus, PCSK9 or a factor acted upon by PCSK9, is secreted from the transfected cells and degrades LDLR both in transfected and untransfected cells.


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