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Human Molecular Genetics Advance Access originally published online on March 28, 2006
Human Molecular Genetics 2006 15(9):1551-1558; doi:10.1093/hmg/ddl077
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

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

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

* To whom correspondence should be addressed. Tel: +47 23075580; Fax: +47 23075561; Email: knut.erik.berge{at}rikshospitalet.no

Received December 23, 2005; Revised March 14, 2006; Accepted March 22, 2006

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is involved in the post-transcriptional regulation of the low-density lipoprotein (LDL) receptors (LDLR). Mutations in the PCSK9 gene have been associated with both 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 with 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 with 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 min 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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